Since 1975, the incidence of obesity has increased to epidemic proportions, and the number of patients with obesity has quadrupled. Obesity is a major risk factor for developing other serious diseases, such as type 2 diabetes mellitus, hypertension, and cardiovascular diseases. Recent epidemiologic studies have defined obesity as a risk factor for the development of neurodegenerative diseases, such as Alzheimer’s disease (AD) and other types of dementia. Despite all these serious comorbidities associated with obesity, there is still a lack of effective antiobesity treatment. Promising candidates for the treatment of obesity are anorexigenic neuropeptides, which are peptides produced by neurons in brain areas implicated in food intake regulation, such as the hypothalamus or the brainstem. These peptides efficiently reduce food intake and body weight. Moreover, because of the proven interconnection between obesity and the risk of developing AD, the potential neuroprotective effects of these two agents in animal models of neurodegeneration have been examined. The objective of this review was to explore anorexigenic neuropeptides produced and acting within the brain, emphasizing their potential not only for the treatment of obesity but also for the treatment of neurodegenerative disorders.

The regulation of food intake and energy homeostasis is a very complex process in which both central and peripheral mechanisms are involved [1]. The central nervous system (CNS), mainly the hypothalamus, is a key regulator of energy homeostasis and is responsible for coordinating physiological processes related to hunger and satiety to maintain energy balance through long-term and short-term signals [2]. These signals are integrated and further processed in the arcuate nucleus (ARC) which is a nucleus at the base of the third ventricle adjacent to the media eminence (ME), one of the circumventricular organs with fenestrated capillaries that allows the transport of different molecules and hormones from the periphery to the brain [3,4]. The ARC contains two distinct populations of neurons with antagonistic properties. The first population produces food intake-stimulating orexigenic neuropeptides, such as neuropeptide Y (NPY) and agouti-related peptide (AgRP), while the second population produces food intake suppressing anorexigenic pro-opiomelanocortin (POMC) and cocaine- and amphetamine-regulated transcript (CART) peptide [5]. One of the peripheral hormones that influence the expression of these neuropeptides in the ARC is leptin, the main regulator of energy balance produced in white adipose tissue (WAT) [6]. Its level in the blood plasma is proportional to the total amount of WAT [7]. Leptin decreases food intake by inhibiting orexigenic NPY/AgRP neurons and simultaneously stimulating anorexigenic POMC/CART neurons [8]. Moreover, leptin decreases the accumulation of fat in the body [9]. This effect of leptin is an example of cooperation among peptides from the periphery and neuropeptides (Figure 1). Another important peripheral hormone that regulates ARC neuropeptides is ghrelin, the only known peripheral orexigenic compound produced in the stomach [10]. Other anorexigenic peptide hormones important for the regulation of food intake, such as amylin [11], cholecystokinin (CCK) [12], glucagon-like peptide 1 (GLP-1) [13], or peptide YY (PYY) [14], are secreted in the periphery (reviewed [15–17]). However, the objective of this review is to focus on neuropeptides, defined as peptides produced within the nervous system that are released by various populations of neurons and function within the brain.

Scheme of peptides involved in food intake regulation

Figure 1
Scheme of peptides involved in food intake regulation

Food intake regulating peptides are produced in the periphery, as well as in the brain. The main regulators of energy homeostasis are anorexigenic (food intake lowering) leptin, produced by white adipose tissue, and orexigenic (food intake stimulating) ghrelin, produced by the stomach. Many other anorexigenic hormones are produced in the gastrointestinal tract, for example, amylin, cholecystokinin (CCK), glucagon-like peptide 1 (GLP-1), or peptide YY (PYY). To induce biological effects, these peptides must penetrate to the brain; either through nervus vagus to the nucleus of the solitary tract (NTS) or through the blood–brain barrier (BBB) to the hypothalamus that is the main center of food intake regulation. In the arcuate nucleus (ARC), located at the base of the third ventricle (3V) adjacent to the media eminence (ME), two distinct populations of neurons regulate food intake with antagonistic effects: anorexigenic pro-opiomelanocortin (POMC) and cocaine- and amphetamine-regulated transcript (CART) peptide, alongside orexigenic neuropeptide Y (NPY) and agouti-related peptide (AgRP). These neuronal populations project to other hypothalamic nuclei, such as ventromedial nucleus (VMN), dorsomedial nucleus (DMN), lateral hypothalamic area (LHA), and paraventricular nucleus (PVN), where are expressed other anorexigenic (corticotropin-releasing hormone [CRH], neuropeptide FF [NPFF], pituitary adenylate cyclase-activating peptide [PACAP], prolactin-releasing peptide [PrRP], and thyrotropin-releasing hormone [TRH]) or orexigenic neuropeptides (galanin, melanin-concentrating hormone [MCH], orexins).

Figure 1
Scheme of peptides involved in food intake regulation

Food intake regulating peptides are produced in the periphery, as well as in the brain. The main regulators of energy homeostasis are anorexigenic (food intake lowering) leptin, produced by white adipose tissue, and orexigenic (food intake stimulating) ghrelin, produced by the stomach. Many other anorexigenic hormones are produced in the gastrointestinal tract, for example, amylin, cholecystokinin (CCK), glucagon-like peptide 1 (GLP-1), or peptide YY (PYY). To induce biological effects, these peptides must penetrate to the brain; either through nervus vagus to the nucleus of the solitary tract (NTS) or through the blood–brain barrier (BBB) to the hypothalamus that is the main center of food intake regulation. In the arcuate nucleus (ARC), located at the base of the third ventricle (3V) adjacent to the media eminence (ME), two distinct populations of neurons regulate food intake with antagonistic effects: anorexigenic pro-opiomelanocortin (POMC) and cocaine- and amphetamine-regulated transcript (CART) peptide, alongside orexigenic neuropeptide Y (NPY) and agouti-related peptide (AgRP). These neuronal populations project to other hypothalamic nuclei, such as ventromedial nucleus (VMN), dorsomedial nucleus (DMN), lateral hypothalamic area (LHA), and paraventricular nucleus (PVN), where are expressed other anorexigenic (corticotropin-releasing hormone [CRH], neuropeptide FF [NPFF], pituitary adenylate cyclase-activating peptide [PACAP], prolactin-releasing peptide [PrRP], and thyrotropin-releasing hormone [TRH]) or orexigenic neuropeptides (galanin, melanin-concentrating hormone [MCH], orexins).

Close modal

Neuropeptides produced from the ARC influence other hypothalamic areas, such as the paraventricular nucleus (PVN), ventromedial nucleus (VMN), dorsomedial hypothalamic nucleus (DMH), and lateral hypothalamic area (LHA) thereby affecting the release of other neuropeptides, both orexigenic (galanin, melanin-concentrating hormone [MCH], and orexins) [18–20] and anorexigenic (corticotropin-releasing hormone [CRH], pituitary adenylate cyclase-activating peptide [PACAP], prolactin-releasing peptide [PrRP], and thyrotropin-releasing hormone [TRH]) [21–25]. From these areas the impulses are projected to the thalamus [26] and are integrated with signals from the brainstem, mainly from the nucleus of the solitary tract (NTS) [27]. When the balance between energy input and output works, physiological equilibrium is maintained. There is currently no effective system for monitoring the caloric intake of individual organs and tissues. Consequently, monitoring fat store bulkiness could be an appropriate approach; if these stores remain unchanged, the energy balance is satisfactory [28]. However, if there is excess energy stored in fat tissue, obesity and its associated comorbidities, such as type 2 diabetes mellitus (T2DM), hypertension, cardiovascular diseases, and metabolic syndrome [8,29,30], develop. Recently, obesity has also been associated with the development of neurodegenerative diseases [31] representing a significant and escalating global challenge. Typically, neurodegenerative diseases exhibit delayed onset, and progressive clinical symptoms and are characterized by neuronal loss [32]. This neuronal loss is known as brain atrophy and leads to memory impairment and dementia [33,34]. Among all neurodegenerative diseases, the most common type is Alzheimer’s disease (AD), which accounts for 60–80% of all cases of dementia according to the World Health Organization [35]. AD is characterized by presence of senile plaques formed by amyloid-β (Aβ), Tau protein hyperphosphorylation, increased neuroinflammation, and decreased synaptogenesis and neurogenesis in the brain [36]. In dementias, including AD, neurodegeneration is associated with aging, leptin and insulin resistance [37,38], inflammation mediated by cytokines [39], oxidative and cellular stress [40], cell death, vascular destruction [41], or dysregulation of the energy balance and metabolism of neuropeptides involved in food intake regulation [42]. These features are also observed in T2DM [43], metabolic syndrome [44], and nonalcoholic fatty liver disease [45]. Therefore, these diseases could be managed through similar, if not identical, therapeutic strategies. Thus, drugs initially developed for obesity treatment might also be useful for the treatment of AD [46], supporting the critical role of neuropeptides in the regulation of neuronal activity [47,48].

While central administration of anorexigenic neuropeptides efficiently decreases food intake and body weight, peripheral application triggers no response due to the inability of neuropeptides to penetrate the brain, where their receptors are expressed. To achieve central biological effects after peripheral administration, such as the abovementioned decrease in food intake, it is necessary to modify neuropeptides to enhance their stability and bioavailability. One example of the improved properties of modified peptides is long-lasting receptor agonists of GLP-1, such as liraglutide, exenatide or lixisenatide, which are on the market as antidiabetic and antiobesity drugs, and currently, their neuroprotective properties are also being investigated in clinical trials [49,50]. In preclinical studies, treatment with liraglutide reduced Aβ plaques, Tau hyperphosphorylation, and neuroinflammation. Additionally, it increases synaptic plasticity, neurogenesis and enhanced memory [51–54]. However, manipulating the central neuropeptide system poses a real therapeutic challenge, as peripherally injected neuropeptides need to access the brain without causing any side effects.

The objective of this review is to summarize the current knowledge on anorexigenic neuropeptides that are produced and acting within the brain, and their modified analogs capable to act centrally after peripheral administration in animal preclinical models with an emphasis on their possible use for treating obesity and neurodegenerative disorders.

Orexigenic neuropeptides, such as NPY, AgRP, MCH, orexins, and galanin, stimulate food intake. Despite their opposite effects on the food intake regulation, orexigenic peptides, like anorexigenic peptides, have shown neuroprotective effects on preclinical models of neurodegenerative diseases. However, they are not the focus of this review.

Decreased NPY levels in different brain regions and plasma have been described in several preclinical models of AD, as well as in patients with AD [55]. NPY can function as an antiapoptotic, anti-inflammatory and neuroprotective agent, as reviewed in [48,56]. Moreover, NPY, implicated in stress response, anxiety, and cognition, also plays an important neuroprotective role in neurodegenerative diseases like Alzheimer’s, Parkinson’s, and Huntington’s disease, where stress is a contributing factor [57]. In the Aβ mouse model of AD, a sole intracerebroventricular (ICV) injection of NPY mitigates depressive-like behavior, spatial memory deficits, and oxidative stress induced by Aβ administration [58]. In addition to its role in regulating energy balance, AgRP, produced by AgRP/NPY neurons, exerts influence on various cellular processes. Notably, the ubiquitin proteasome system, crucial for the targeted degradation of short-lived proteins, is typically downregulated in AD. Lee at al. [59] demonstrated that the recombinant human AgRP protein increases proteasome activity in SH-SY5Y cells. Additionally, in 5xFAD mice, administration of AgRP protein led to an increase in proteasome activity and inhibited the accumulation of ubiquitin-conjugated proteins. This suggests that AgRP has the potential to decrease abnormal protein aggregation, thereby potentially slowing down the clinical progression of various neurodegenerative diseases [59].

The orexigenic neuropeptide MCH is produced in LHA neurons that further project to the hippocampal cornu ammonis (CA) 1 area, which is connected to memory formation. Mice with knock-in Swedish mutation in amyloid precursor protein (APP), which leads to the development of the familial form of AD (APPNL-G-F mice), presented a decreased MCH level and subsequent aberrant excitation of hippocampal neurons. Thus, MCH deregulation may be involved in the development of the early stages of AD [60]. In the study by Oh et al. [61], MCH peptide was intranasally administered to scopolamine-induced memory-impaired mice to assess acute effects and to AD mouse models to investigate chronic effects. MCH ameliorated memory impairment in these models and reduced soluble Aβ levels in the cerebral cortex of APP/PS1 transgenic mice. Additionally, MCH enhanced long-term potentiation in the hippocampus of both wild-type and 5xFAD AD mouse models [61]. The administration of MCH peptide into the hippocampus and amygdala enhanced the memory performance of rats [62] and reverse the amnesic effects induced by a nitric oxide synthase inhibitor [63], a known disruptor of hippocampal plasticity. N-methyl-D-aspartate (NMDA) receptors play a pivotal role in the remarkable plasticity exhibited by the hippocampus [64] and are fundamentally implicated in the neural mechanisms that underlie specific forms of learning. In hippocampal slices from rats treated with MCH and subjected to a memory task, an increase in the expression of NMDA receptor subunits crucial for synaptic plasticity was observed [64].

Orexin A and orexin B produced in the LHA are involved in sleep/wake processes, appetite, drug addiction and cognitive processes. Orexins also have neuroprotective and anti-inflammatory properties, as reviewed previously [65,66]. Previous studies have indicated that orexin-A exhibits protective effects in cellular models of Parkinson’s disease. Liu et al. revealed that orexin-A mitigated the loss of dopaminergic neurons and the reduction in tyrosine hydroxylase expression in the substantia nigra in a mouse model of Parkinson’s disease. Orexin-A improved both motor activity and spatial memory in this mouse model and elevated the protein levels of brain-derived neurotrophic factor (BDNF), which promotes neuroprotection and neuroregeneration, in dopaminergic neurons of the substantia nigra [67].

In addition to its orexigenic effect, galanin is involved in a broad range of physiological functions including effects on memory, learning and neurogenesis in the hippocampus [68]. The intranasal coadministration of galanin receptor-2 (GALR2) agonist (M1145) and NPY receptor 1 (NPY1R) agonist improved spatial memory in the Sprague-Dawley rats [68]. Subsequent study revealed a sustained increase in neurogenesis in the dorsal dentate gyrus following ICV administration of GALR2 and NPY1R agonists. Simultaneous delivery of the M1145 and the NPY1R agonist promoted neuroblast proliferation and improvement in object-in-place memory [69]. Additionally, galanin receptor-2/3 agonist (Gal 2-11) induced proliferation of hippocampal precursor cells, thus directly affected hippocampal neurogenesis, impaired in AD, through production of granule cell neurons of the dentate gyrus [70].

Anorexigenic neuropeptides inhibiting food intake include POMC, CART peptide (CARTp), PACAP, PrRP, neuropeptide FF (NPFF), CRH, and THR. The potential of these peptides in the treatment of obesity and neurodegeneration is described in separate chapters. The order was determined according to the expression in individual hypothalamic nuclei.

Melanocortin system

The melanocortin system includes multiple peptides such as α, β and γ-melanocyte-stimulating hormone (MSH), adrenocorticotrophic hormone (ACTH), and β-lipotropin, which are derived from the precursor POMC [71,72]. The precursor protein POMC consists of three main domains whose different cleavages by proprotein convertases produce different molecules, such as γ-MSH from the N-terminal region, ACTH from the central region, which can be further cleaved to α-MSH, and β-MSH and β-endorphin cleaved from β-lipotropin from the C-terminal domain [73]. The posttranslational processing of POMC occurs in a tissue-specific manner and results in diverse biological functions. The POMC system controls nervous, behavioral, endocrine, and immune functions and has a regulatory and homeostatic roles [71].

These molecules are cleaved from POMC and share the common tetrapeptide core sequence His-Phe-Arg-Trp which interacts with and activates melanocortin receptors (MCRs). MCRs are G protein-coupled receptors (GPCR) that include five receptor variants with multiple physiological functions. MC1R regulates pigmentation in melanocytes, MC2R activates glucocorticoid biosynthesis in the adrenal cortex, MC3R and MC4R influence energy homeostasis in the central nervous system, and MC5R regulates the synthesis and secretion of exocrine gland products [74,75]. ACTH and α-MSH can activate MC1R, MC3R, MC4R, and MC5R. However, MC2R can be activated by ACTH but not any other melanocortin [74,76]. Additionally, MC3R has a very high binding capacity for γ-MSH, while MC4R has a very high binding capacity for α- and β-MSH [77]. Orexigenic AgRP is a natural antagonist of MC3R and MC4R activity [78,79].

POMC is highly expressed in endocrine cells of the pituitary gland and neurons of the hypothalamic ARC [75,80]. Melanocortins are part of the anorexigenic system that decreases appetite and food intake, therefore they play an important role in the regulation of body weight homeostasis and energy balance. The primary effects of POMC-derived peptides on feeding and body weight are mediated by MSH peptides and their effects on MC3R and MC4R [81]. MC3R and MC4R have been investigated as promising targets for anti-obesity drugs [82–84]. Humans deficient in POMC or MC4R are hyperphagic and severely obese [85,86]. Additionally, MC3R mutation variants cause robust obesity in humans [77]. An obese phenotype is also evident in knockout (KO) MC3R and MC4R mice. While MC4R KO mice exhibit hyperphagia and develop T2DM, MC3R KO mice are not hyperphagic and have a normal metabolic response [87].

α-MSH, produced in the ARC and acting at MC4R in the PVN is important for the regulation of food intake and energy balance and is one of the main mediators of the effects of leptin [72]. The ICV administration of melanotan II (MTII) a cyclic melanocortin agonist with the sequence Ac-Nle4-c[Asp5,D-Phe7,Lys10]α-MSH- [4–10]-NH2 resulted in a significant reduction in food intake and body weight in male Sprague-Dawley rats fed a high-fat diet (HFD) [88]. Interestingly, consumption of a HFD decreases signaling through the melanocortin system. Rats maintained on a HFD were less sensitive to the inhibition of food intake induced by MTII [89]. MTII is a potent agonist of both MC3R and MC4R, and when MTII is administered via the ICV, it inhibits acute food intake in fasted mice [90] but has no effect on food intake in fasted Mc4r–/– mice [91,92]. Another MC4R peptide agonist, the lipidized analog of α-MSH [93], called MC4-NN1-0182, was investigated in rats with diet-induced obesity (DIO) and DIO minipigs. Long-term treatment with MC4-NN1-0182 resulted in a decrease in food intake and body weight [94]. Moreover, DIO rats exhibit reduced levels of leptin, cholesterol, and insulin, with a slight increase in oxygen consumption [94]. α-MSH activates a thermogenic gene program and increases the mitochondrial respiratory rate in adipocytes and inguinal WAT of DIO mice. Without affecting food intake, peripheral administration of α-MSH decreased body weight and inguinal WAT mass [95].

Another melanocortin analog, cyclic peptide setmelanotide (also known as BIM-22493), demonstrated a reduction in acute food intake in fasted mice. Interestingly, the inhibition of refeeding after an overnight fast by BIM-22493 was dependent on functional MC4R and did not require MC3R [96]. Chronic treatment of DIO mice with BIM-22493 resulted in weight loss and improvements in hyperinsulinemia and fatty liver. However, treatment with BIM-22511 did not impact body weight in MC4R KO mice but did reduce body weight in MC3R KO mice. Additionally, chronic treatment with BIM-22511 did not improve hepatosteatosis in MC4R KO mice and did not affect hepatic lipogenic gene expression. MC4R is necessary for melanocortin agonist-induced weight loss and improvements in liver metabolism but is not required for improvements in hyperinsulinemia [96].

α-MSH and its analogs have been proposed to exhibit neuroprotective and anti-inflammatory effects and represent a potential strategy for treating AD [97]. Concentrations of α-MSH in the brain and cerebrospinal fluid of AD patients were reduced, correlating with cognitive dysfunction [98,99]. Activation of POMC-derived neuropeptides and MCRs has previously been shown to rescue the impairment of synaptic plasticity in a mouse model of AD. Treatment with α-MSH preserved the expression of the GABAergic marker GAD67 (glutamic acid decarboxylase 67) promoted the survival of GABAergic GAD67+ inhibitory interneurons in the hippocampus and improved spatial memory in the TgCRND8 mouse model of AD with Swedish and Indiana mutations in APP [100]. In ischemic rats, which display a reduced number of neurons with pathological morphological changes in the CA1 pyramidal cell layer of the hippocampus, treatment with α-MSH leads to an increase in the number of viable hippocampal neurons. Additionally, α-MSH decreases glial activation, as indicated by the reduction in glial fibrillary acidic protein (GFAP), an astrocyte marker that is markedly elevated in ischemic rats. Therefore, the neuroprotective effect of α-MSH could be attributed to the reduction of damage caused by reperfusion. However, further studies will be necessary to determine whether the neuroprotective effect of α-MSH is mediated by its anti-inflammatory actions [101].

The melanocortin analog [Nle4, D-Phe7]α-MSH (NDP-α-MSH) has been shown to improved learning and memory, as well as increase neurogenesis in Mongolian gerbils [102]. The effect of chronic administration of NDP-α-MSH was investigated in several mouse models of AD – in 3xTg mice, a model of AD containing three human mutations, APPSwe, presenilin 1 (PS1)M146V, and TauP301L [103,104]; in Tg2576 mice carrying the APPSWE mutation [105,106]; and in 5XFAD mice with 5 mutations connected to AD-Swedish (K670N/M671L), Florida (I716V), and London (V717I) mutations in APP, and the M146L and L286V mutations in PS1 [104]. NDP-α-MSH improved spatial memory in Morris water maze (MWM) in all mentioned AD mouse models [103–106]. NDP-α-MSH further reduced the level of Aβ deposits in Tg2576 [105] and in 30-week-old 3xTg mice [103]. However, the level of Aβ deposits or astrocytic reactivity were not influenced by NDP-α-MSH in 9- and 14-month-old 3xTg mice or in 5XFAD mice [104]. While NDP-α-MSH did not influence microglial reactivity, as indicated by ionized calcium binding adaptor molecule 1 (Iba1) staining, in 5XFAD mice, it reduced microglial reactivity in the CA3 region in 3xTg mice [104]. Treatment also attenuated Tau hyperphosphorylation at different epitopes in 3xTg and 5XFAD mice [103,104] and reduced the level of p38 mitogen-activated protein kinase (MAPK), which is a kinase that is overactivated in patients with AD [107]. Finally, NDP-α-MSH decreased neuronal loss and increased hippocampal expression of the immediate early response gene Zif268, suggesting increased synaptogenesis [103,105]. Moreover, it increased the number of bromodeoxyuridine immunoreactive cells, a marker of cell proliferation, which are colocalized with the markers of mature neurons NeuN and Zif268 in the hippocampus of Tg2576 mice [106]. The central administration of another MCR agonist [d-Tyr4]-melanotan II, reduced Aβ levels, improved inflammation and astrocytic activation in the hippocampus and suppressed microglial activation in APP/PS1 mice. It significantly reduced 6E10-immunostained amyloid plaques and decreased levels of both insoluble and soluble Aβ, with reduced levels of isomers Aβx–42 and Aβx–40. Additionally, the treatment lowered the elevated expression of pro-inflammatory factors interleukin-1β (IL-1β) and interleukin-6 (IL-6), as well as anti-inflammatory cytokine intercellular adhesion molecule 1 (Icam1). Moreover, [d-Tyr4]-melanotan II reduced the increased expression and immunoreactivity of GFAP, particularly in the CA1 zone, and decreased microglial density in the hippocampus [108].

Considering these results, which are summarized in Table 1 and in Table 2, α-MSH treatment represents a strategy for treating obesity, improving cognitive function, and exerting neuroprotective effects along with increased neurogenesis.

Table 1
Effect on food intake and body weight after chronic administration of neuropeptides or their modified analogs in DIO rodent models
Animal model
HFD: starting age and weeks of feeding
Intervention
Compound/ dose/ injection/ duration
Effects
Increased ↑
Decreased ↓
Reference
 Melanocortins   
Sprague-Dawley rats ♂
HFD: from 6th week, 12 weeks 
MTII
0.5 nmol/rat, ICV
once 
Reduced food intake
Reduced body weight 
[88
Long-Evans rats ♂
HFD: from 6th week, 8 weeks 
MTII
0.1, 0.3, 1.0 nmol/rat, ICV
once 
Reduced food intake [89
Sprague-Dawley rats ♂
HFD: from 7 to 8th week, 10 weeks
Göttingen minipigs ♀
NS
ad libitum fed half a year 
MC4-NN1-0182
0.5 ml/kg, SC
23 days
30 mg/pig at day 0, SC
10 mg/pig every other day
58 days 
Reduced food intake
Reduced body weight and adipose tissue
Leptin, cholesterol, and insulin ↓
Reduced food intake
Reduced body weight 
[94
C57BL/6 mice ♂
HFD: from 10th week, 10 weeks 
α-MSH
150 μg/kg, IP
14 days 
Reduced body weight and ingWAT
Ucp1 mRNA ↑
Pgc-1α mRNA ↑
Thermoregulatory-related genes ↑ 
[95
C57BL/J DIO mice ♂
HFD: NS
MC3R KO mice ♀
STD: NS
MC4R KO mice ♀
STD: NS 
BIM-22493
300 nmol/kg/day, SC osmotic pump
14 days
BIM-22511
100 nmol/kg/day, SC osmotic pump
14 days
BIM-22511
100 nmol/kg/day, SC osmotic pump
14 days 
Reduced food intake
Reduced body weight
Leptin, cholesterol, and insulin ↓
Improved liver steatosis
Reduced body weight
No reduction of body weight
Insulin ↓ 
[96
 CART peptide   
Long-Evans rats ♂
NS 
CARTp (55-102)
9 µg/day, ICV
6 days 
Reduced food intake
Reduced body weight
Leptin, insulin, glucose ↓ 
[141
Sprague-Dawley rats ♂
HFD: NS, 3 weeks 
CARTp (55-102)
500 pmol/each
two ICV injections 
Reduced food intake
Lipid metabolism ↑
NEFA ↑ 
[142
 PrRP   
C57BL/6 mice ♂
HFD: from 8th week, 12 weeks 
Palm-PrRP31 or Myr-PrRP20
5 mg/kg, SC
twice a day
14 days 
Reduced food intake
Reduced body weight
Reduced amount of WAT
Leptin ↓, Insulin (only palm-PrRP31) ↓
Fasn mRNA↓ 
[177
C57BL/6 mice ♂
HFD: from 8th week, 12 weeks 
Palm11-PrRP31
5 mg/kg, SC
twice a day
2 weeks 
Reduced food intake
Reduced body weight
Reduced amount of scWAT
Insulin, Leptin, TAG, FFA, cholesterol ↓
Fasn m RNA in WAT ↓
Ucp1 mRNA in BAT ↑ 
[179
C57BL/6 mice ♂
HFD: from 8th week, 12 weeks 
Palm11-PrRP31
5 mg/kg, SC
twice a day
28 days, or 14 days + 14 days wash-out 
Reduced food intake of both groups
Reduced body weight of both groups
Reduced amount of scWAT
Leptin ↓
pAkt Ser473, p-ERK, PI3K in the hypothalamus ↑
Ucp1 mRNA in BAT ↑ 
[180
Wistar Kyoto rats ♂
HFD: from 8th week, 15 weeks 
Palm11-PrRP31
5 mg/kg, IP
once a day
21 days 
Reduced body weight
Reduced amount of WAT
Improved OGTT
Acaca mRNA, Fasn mRNA in scWAT ↓ 
[181
Sprague–Dawley rats ♂
HFD: from 7th to 9th week, 24 weeks 
Palm-PrRP31
1 or 5 mg/kg, IP
once a day
15 days 
Reduced food intake
Reduced body weight 
[182
Wistar Kyoto rats ♂
HFD: from 8th week, 52 weeks 
Palm11-PrRP31
5 mg/kg, IP
once a day 5 days/week
6 weeks 
Reduced food intake
Reduced body weight
Improved OGTT
Leptin ↓ 
[183
DIO mice ♂
HFD: from 6th week, 18 weeks 
18-S4 (analog of PrRP31, agonist of GPR10 receptor)
0.5 mg/kg, SC
12 days 
Reduced body weight [185
C57BL/6 J mice ♂
HFD: 5th week, 47 weeks 
GUB03385
1.250 nmol/kg, SC
7 days + 7 days wash-out 
Reduced food intake
Reduced body weight 
[187
 NPFF   
C57BL/6 mice ♂
HFD: from 8th week, 12 weeks 
NPFF
4 nmol/kg, IP
18 days 
No decreased body weight
No decreased food intake
No decreased weight of AT
glucose tolerance, AT insulin sensitivity ↑
mRNA Npffr2 ↑ 
[216
C57BL/6N mice ♂
HFD: from 8th week, 4 months 
oct-1DMe
10 mg/kg, SC
28 days 
No decreased body weight
No decreased food intake 
[217
 TRH   
CD1 mice ♀
NS 
Synthetic TRH (5-Oxo-L-prolyl-L-histidyl-L-prolinamide monotartrate monohydrate)
0.3 mg/kg, IP
26 days + 30 days wash-out 
Reduced food intake
Reduced body weight, however, increased body weight during wash-out period
Leptin, cholesterol, TAG ↓ 
[262
Animal model
HFD: starting age and weeks of feeding
Intervention
Compound/ dose/ injection/ duration
Effects
Increased ↑
Decreased ↓
Reference
 Melanocortins   
Sprague-Dawley rats ♂
HFD: from 6th week, 12 weeks 
MTII
0.5 nmol/rat, ICV
once 
Reduced food intake
Reduced body weight 
[88
Long-Evans rats ♂
HFD: from 6th week, 8 weeks 
MTII
0.1, 0.3, 1.0 nmol/rat, ICV
once 
Reduced food intake [89
Sprague-Dawley rats ♂
HFD: from 7 to 8th week, 10 weeks
Göttingen minipigs ♀
NS
ad libitum fed half a year 
MC4-NN1-0182
0.5 ml/kg, SC
23 days
30 mg/pig at day 0, SC
10 mg/pig every other day
58 days 
Reduced food intake
Reduced body weight and adipose tissue
Leptin, cholesterol, and insulin ↓
Reduced food intake
Reduced body weight 
[94
C57BL/6 mice ♂
HFD: from 10th week, 10 weeks 
α-MSH
150 μg/kg, IP
14 days 
Reduced body weight and ingWAT
Ucp1 mRNA ↑
Pgc-1α mRNA ↑
Thermoregulatory-related genes ↑ 
[95
C57BL/J DIO mice ♂
HFD: NS
MC3R KO mice ♀
STD: NS
MC4R KO mice ♀
STD: NS 
BIM-22493
300 nmol/kg/day, SC osmotic pump
14 days
BIM-22511
100 nmol/kg/day, SC osmotic pump
14 days
BIM-22511
100 nmol/kg/day, SC osmotic pump
14 days 
Reduced food intake
Reduced body weight
Leptin, cholesterol, and insulin ↓
Improved liver steatosis
Reduced body weight
No reduction of body weight
Insulin ↓ 
[96
 CART peptide   
Long-Evans rats ♂
NS 
CARTp (55-102)
9 µg/day, ICV
6 days 
Reduced food intake
Reduced body weight
Leptin, insulin, glucose ↓ 
[141
Sprague-Dawley rats ♂
HFD: NS, 3 weeks 
CARTp (55-102)
500 pmol/each
two ICV injections 
Reduced food intake
Lipid metabolism ↑
NEFA ↑ 
[142
 PrRP   
C57BL/6 mice ♂
HFD: from 8th week, 12 weeks 
Palm-PrRP31 or Myr-PrRP20
5 mg/kg, SC
twice a day
14 days 
Reduced food intake
Reduced body weight
Reduced amount of WAT
Leptin ↓, Insulin (only palm-PrRP31) ↓
Fasn mRNA↓ 
[177
C57BL/6 mice ♂
HFD: from 8th week, 12 weeks 
Palm11-PrRP31
5 mg/kg, SC
twice a day
2 weeks 
Reduced food intake
Reduced body weight
Reduced amount of scWAT
Insulin, Leptin, TAG, FFA, cholesterol ↓
Fasn m RNA in WAT ↓
Ucp1 mRNA in BAT ↑ 
[179
C57BL/6 mice ♂
HFD: from 8th week, 12 weeks 
Palm11-PrRP31
5 mg/kg, SC
twice a day
28 days, or 14 days + 14 days wash-out 
Reduced food intake of both groups
Reduced body weight of both groups
Reduced amount of scWAT
Leptin ↓
pAkt Ser473, p-ERK, PI3K in the hypothalamus ↑
Ucp1 mRNA in BAT ↑ 
[180
Wistar Kyoto rats ♂
HFD: from 8th week, 15 weeks 
Palm11-PrRP31
5 mg/kg, IP
once a day
21 days 
Reduced body weight
Reduced amount of WAT
Improved OGTT
Acaca mRNA, Fasn mRNA in scWAT ↓ 
[181
Sprague–Dawley rats ♂
HFD: from 7th to 9th week, 24 weeks 
Palm-PrRP31
1 or 5 mg/kg, IP
once a day
15 days 
Reduced food intake
Reduced body weight 
[182
Wistar Kyoto rats ♂
HFD: from 8th week, 52 weeks 
Palm11-PrRP31
5 mg/kg, IP
once a day 5 days/week
6 weeks 
Reduced food intake
Reduced body weight
Improved OGTT
Leptin ↓ 
[183
DIO mice ♂
HFD: from 6th week, 18 weeks 
18-S4 (analog of PrRP31, agonist of GPR10 receptor)
0.5 mg/kg, SC
12 days 
Reduced body weight [185
C57BL/6 J mice ♂
HFD: 5th week, 47 weeks 
GUB03385
1.250 nmol/kg, SC
7 days + 7 days wash-out 
Reduced food intake
Reduced body weight 
[187
 NPFF   
C57BL/6 mice ♂
HFD: from 8th week, 12 weeks 
NPFF
4 nmol/kg, IP
18 days 
No decreased body weight
No decreased food intake
No decreased weight of AT
glucose tolerance, AT insulin sensitivity ↑
mRNA Npffr2 ↑ 
[216
C57BL/6N mice ♂
HFD: from 8th week, 4 months 
oct-1DMe
10 mg/kg, SC
28 days 
No decreased body weight
No decreased food intake 
[217
 TRH   
CD1 mice ♀
NS 
Synthetic TRH (5-Oxo-L-prolyl-L-histidyl-L-prolinamide monotartrate monohydrate)
0.3 mg/kg, IP
26 days + 30 days wash-out 
Reduced food intake
Reduced body weight, however, increased body weight during wash-out period
Leptin, cholesterol, TAG ↓ 
[262

Abbreviations: Acaca, acetyl-CoA carboxylase; AT, adipose tissue; BAT, brown adipose tissue; CART, cocaine- and amphetamine-regulated transcript; DIO, diet-induced obesity; ERK, extracellular signal-regulated kinase; Fasn, fatty acid synthase; FFA, free fatty acids; HFD, high-fat diet; ICV, intracerebroventricular; ing, inguinal; IP, intraperitoneal; MCR, melanocortin receptor; MSH, melanocyte-stimulating hormone; myr, myristoyl; NS, not specified; Npffr2, neuropeptide FF receptor 2; oct, octanoyl; OGTT, oral glucose tolerance test; palm, palmitoyl; Pgc-1α, peroxisome proliferator-activated receptor-γ coactivator; PI3K, phosphoinositide 3-kinases; PrRP, prolactin-releasing peptide; SC, subcutaneous; TAG, triacylglycerols; TRH, thyrotropin-releasing hormone; Ucp1, uncoupling protein 1; WAT, white adipose tissue; ♂, male; ♀, female

Table 2
Pharmacological interventions of neuropeptides in rodent models of AD-like pathology
Animal model
Starting age
Intervention
Compound/dose/
injection/duration
Effect of memory/Behavioral testEffect in hippocampus/cortexMarker
Increased ↑
Decreased ↓
Reference
 Melanocortins     
TgCRND8 ♂, ♀
20 weeks old 
α-MSH
0.5 mg/kg IP daily
28 days 
OF: normal anxiety, no effect on locomotion
Y maze: preserved spatial memory 
Increased synaptic plasticity GAD67 ↑ [100
Sprague-Dawley rats ♂
Transient global cerebral ischemia
NS age 
α-MSH
0.5 mg/kg IP
30 min post-ischemia, and at 24, 48, 72, 96 h 
 Viable neurons in the CA1 pyramidal cell layer
Higher number of viable neurons 
GFAP-labeled cells ↓ intensity [101
Mongolian gerbils ♂
Transient global brain ischemia
NS age 
NDP-α-MSH
340 µg/kg IP
2 × daily
11 days 
MWM: improved learning and memory Prevents DNA fragmentation in the hippocampal cells BrdU-labeled cells ↑
BrdU-NeuN+ ↑
Zif268 ↑ 
[102
3xTg mice ♂
12 weeks old 
NDP-α-MSH
340 µg/kg IP daily
18 weeks
+/- inhibitor HS024 
MWM: improved learning and memory Decreased Aβ pathology
Reduced Tau phosphorylation
Decreased apoptosis
Reduced neuroinflammation 
Aβ plaques ↓, p-APP Thr668 ↓
p-Tau Thr181, p-Tau Ser396, p-Tau Ser202 ↓
p-p38 ↓, Caspase-3 ↓
IL-1β↓, TNF-α ↓ 
[103
5XFAD mice NS sex
5 and 7 months old
3xTg mice ♂
9 and 12 months old 
NDP-α-MSH
340 mg/kg IP daily
50 days 
MWM: improved spatial memory Microglial reactivity
Reduced AD-related markers 
Iba1 ↓ in 3xTg mice
p-Tau Ser396, p-Tau Ser202, p38 MAPK ↓ in 5XFAD
p-Tau Ser202, p38 MAPK ↓ in 3xTg 
[104
Tg2576 ♂
24 weeks old 
NDP-α-MSH
340 µg/kg IP daily
50 days 
MWM: improved spatial learning and memory Decreased Aβ pathology
Increased synaptic plasticity 
Aβ plaques ↓
Zif268 ↑ 
[105
Tg2576 mice ♂
24 weeks old 
NDP-α-MSH
340 µg/kg IP daily
50 days 
MWM: improves learning and memory Decreased Aβ pathology
Increased neurogenesis
Reduced neuroinflammation 
Aβ plaques ↓
BrdU+ ↑, Zif268 ↑, NeuN ↑
GFAP ↓ 
[106
APP/PS1 mice ♂
6–7 months old 
D-Tyr MTII
ICV Alzet minipumps
2.4 nmol/day
28 days 
 Decreased Aβ pathology
Reduced neuroinflammation
Increased synaptic plasticity 
Aβ plaques ↓
IL-1β ↓, Icam1 ↓
Gfap ↓, Aif1
C3+ GFAP+ astrocytes ↓ 
[108
 CART peptide     
Sprague-Dawley rats ♂
NS age 
CARTp (54-102)
25-100ng/rat/day
4 days
CART antibody
ICV daily 
MWM: improved spatial memory Increased CART-immunoreactive fibers in the hippocampus CART-ir fibers ↑ [143
APP/PS1 mice ♂
8 months old 
CART peptide
IV 0.5 µg/kg 10 days
+ IP 0.5 µg/kg 20 days 
MWM: improved spatial memory Decreased Aβ pathology
Increased synaptic plasticity
Reduced reactive oxygen species 
Aβ plaques ↓
LTP ↑, SYP ↑
ROS ↓ 
[144
APP/PS1 mice ♂
6 months old 
CART peptide
IV 0.5 µg/kg 10 days
+ IP 0.5 µg/kg 20 days 
MWM: improved spatial memory Decreased Aβ pathology
Increased insulin signaling 
Soluble Aβ ↓, Aβ enzymes ↓
Akt ↑ 
[145
APP/PS1 mice ♂
8 months old 
CART peptide
IV 0.5 µg/kg 10 days
+ IP 0.5 µg/kg 20 days 
MWM: improved spatial memory Decreased Aβ pathology
Activation of Aβ-degrading enzymes
Decreased reactive oxygen species 
Aβ plaques ↓
NEP, IDE ↑
ROS level ↓ 
[146
Sprague-Dawley rats ♂ Intrahippocampally injected with Aβ1-42
NS age 
CART (55-102)
Intrahippocampal injection
0.02 µg/hemisphere
5 days 
MWM: improved spatial memory
OF: improved locomotor activity 
Decreased Aβ pathology
Attenuated oxidative stress
Decreased neuronal apoptosis 
Aβ plaques, BACE1 ↓
MDA ↓
T-SOD, GSH, ATP, Nrf2, HO-1, NQO1 ↑
Bcl-2 ↑
Bax, caspase 3, caspase 9 ↑ 
[147
 PACAP     
APP(V717I) mice ♂
3 months old 
PACAP38
IN 10 µg/day
5 days/week
3 months 
NOR: improved memory Increased nonamyloidogenic pathway of APP
Increased expression of BDNF 
Neuroprotective sAPPα ↑
soluble Aβ ↓
BDNF ↑ 
[158
 PrRP     
MSG mice ♂
6 months old 
Palm-PrRP31
SC 5 mg/kg
Liraglutide SC 0.2 mg/kg
Daily, 14 days 
 Reduced Tau phosphorylation
Increased insulin signaling 
p-GSK3β(Ser9) ↑
p-Tau Ser396 ↓, p-Tau Thr231 ↓, p-Tau Thr212 ↓
p-PDK1(Ser241) ↑
p-Akt (Thr308), (Ser473) ↑ 
[188
Thy-Tau22 mice ♀
7 months old 
Palm11-PrRP31
Alzet minipumps SC
5 mg/kg/day
2 months 
Y maze: improved short-term working memory Reduced Tau phosphorylation
Increased synaptic plasticity
Increased insulin signaling 
p-GSK3β(Ser9) ↑, PP2A subC ↑
p- Tau Ser396 ↓, p-Tau Ser404 ↓, p-Tau Thr231 ↓
PSD-95 ↑, SYP ↑
p-Akt (Ser473) ↑, p-Akt (Thr308) ↑ 
[189]
[54
APP/PS1 mice ♂
7 months old
APP/PS1 mice ♂
7 months old 
Palm11-PrRP31
SC 5 mg/kg
Liraglutide SC 0.2 mg/kg
Daily, 2 months
Palm11-PrRP31
SC 5 mg/kg
Daily, 2 months 
 Decreased Aβ pathology
Decreased neuroinflammation
Reduced Tau phosphorylation
Mild increase in neurogenesis
Increased synaptogenesis
Reduced Aβ in cerebellum
Reduced microgliosis in cerebellum
Decreased pro-inflammatory proteins in hippocampi
Increased synaptogenesis
Decreased apoptosis 
Aβ plaques ↓
Iba-1 ↓, GFAP ↓
p-Thr231 ↓
DCX ↑
SYP ↑
Aβ plaques ↓
Iba-1 ↓
CD68 ↓, IFNγ ↓
Syntaxin 1A↑, SYP ↑, PSD95 ↑
Bax/Bcl2 ↓ 
[190
 NPFF     
Sprague-Dawley rats ♂
NS age 
NPFF
VTA 1, 2.5, 5, 7.5 or 10 µg/mice 
Cages: reduced locomotion   [225
Wild-type mice (NS strain)
3–4 months old 
NPFF
ICV 1.0 µg/mice
ICV 10 µg/mice 
MWM: spatial acquisition
improved
reduced 
  [226
C57BL/6J mice ♂
3 months old 
1DMe
ICV 1 or 10 nmol 
OL: impaired short-term memory
MWM: impaired long-term memory 
  [227
CFLP mice ♂
NS age 
NPAF
ICV 1.0 µg/mice 
Improved passive
avoidance learning 
  [228
 CRH     
APP/PS1 mice ♂, ♀
1 month old 
R121919 (CRH 1 receptor antagonist)
SC 20 mg/kg
150 days 
MWM: improved spatial memory Decreased Aβ plaque load
Decreased activity of BACE
Increased synaptogenesis 
Aβ plaques ↓
BACE ↓
SYP ↑, MAP2 ↑ 
[244
Tg2576 mice chronically stressed ♂, ♀
4 months 
Antalarmin (CRH 1 receptor antagonist)
20 mg/kg in drinking water, 6 months 
EPM: decreased anxiety-like behavior
Y -maze: improved working memory 
Decreased level of Aβ in chronically stressed mice Aβ plaques ↓, Aβ42 ↓ [245
PS19 mice ♂, stressed for 1 month during the treatment
7 months 
NBI 27914 (CRH 1 receptor antagonist)
SC 10 mg/kg
6 day/week
4 weeks 
Fear conditioning: improved impairment in fear-associated memory Attenuated Tau hyperphosphorylation
Prevented neuronal loss 
AT8 ↓, PHF1 ↓
NeuN ↑ 
[246
Sprague-Dawley rats ♂, ♀ exposed to Isolation-restraint stress
18 months 
R121919 or antalarmin
20 mg/kg mixed in chow diet
3 months 
OF: decreased anxiety
NOR: improved memory
MWM: improved spatial memory 
Increased spine density in cortex
Increased synaptic density 
Spine density ↑
Synaptic density ↑ 
[247
Animal model
Starting age
Intervention
Compound/dose/
injection/duration
Effect of memory/Behavioral testEffect in hippocampus/cortexMarker
Increased ↑
Decreased ↓
Reference
 Melanocortins     
TgCRND8 ♂, ♀
20 weeks old 
α-MSH
0.5 mg/kg IP daily
28 days 
OF: normal anxiety, no effect on locomotion
Y maze: preserved spatial memory 
Increased synaptic plasticity GAD67 ↑ [100
Sprague-Dawley rats ♂
Transient global cerebral ischemia
NS age 
α-MSH
0.5 mg/kg IP
30 min post-ischemia, and at 24, 48, 72, 96 h 
 Viable neurons in the CA1 pyramidal cell layer
Higher number of viable neurons 
GFAP-labeled cells ↓ intensity [101
Mongolian gerbils ♂
Transient global brain ischemia
NS age 
NDP-α-MSH
340 µg/kg IP
2 × daily
11 days 
MWM: improved learning and memory Prevents DNA fragmentation in the hippocampal cells BrdU-labeled cells ↑
BrdU-NeuN+ ↑
Zif268 ↑ 
[102
3xTg mice ♂
12 weeks old 
NDP-α-MSH
340 µg/kg IP daily
18 weeks
+/- inhibitor HS024 
MWM: improved learning and memory Decreased Aβ pathology
Reduced Tau phosphorylation
Decreased apoptosis
Reduced neuroinflammation 
Aβ plaques ↓, p-APP Thr668 ↓
p-Tau Thr181, p-Tau Ser396, p-Tau Ser202 ↓
p-p38 ↓, Caspase-3 ↓
IL-1β↓, TNF-α ↓ 
[103
5XFAD mice NS sex
5 and 7 months old
3xTg mice ♂
9 and 12 months old 
NDP-α-MSH
340 mg/kg IP daily
50 days 
MWM: improved spatial memory Microglial reactivity
Reduced AD-related markers 
Iba1 ↓ in 3xTg mice
p-Tau Ser396, p-Tau Ser202, p38 MAPK ↓ in 5XFAD
p-Tau Ser202, p38 MAPK ↓ in 3xTg 
[104
Tg2576 ♂
24 weeks old 
NDP-α-MSH
340 µg/kg IP daily
50 days 
MWM: improved spatial learning and memory Decreased Aβ pathology
Increased synaptic plasticity 
Aβ plaques ↓
Zif268 ↑ 
[105
Tg2576 mice ♂
24 weeks old 
NDP-α-MSH
340 µg/kg IP daily
50 days 
MWM: improves learning and memory Decreased Aβ pathology
Increased neurogenesis
Reduced neuroinflammation 
Aβ plaques ↓
BrdU+ ↑, Zif268 ↑, NeuN ↑
GFAP ↓ 
[106
APP/PS1 mice ♂
6–7 months old 
D-Tyr MTII
ICV Alzet minipumps
2.4 nmol/day
28 days 
 Decreased Aβ pathology
Reduced neuroinflammation
Increased synaptic plasticity 
Aβ plaques ↓
IL-1β ↓, Icam1 ↓
Gfap ↓, Aif1
C3+ GFAP+ astrocytes ↓ 
[108
 CART peptide     
Sprague-Dawley rats ♂
NS age 
CARTp (54-102)
25-100ng/rat/day
4 days
CART antibody
ICV daily 
MWM: improved spatial memory Increased CART-immunoreactive fibers in the hippocampus CART-ir fibers ↑ [143
APP/PS1 mice ♂
8 months old 
CART peptide
IV 0.5 µg/kg 10 days
+ IP 0.5 µg/kg 20 days 
MWM: improved spatial memory Decreased Aβ pathology
Increased synaptic plasticity
Reduced reactive oxygen species 
Aβ plaques ↓
LTP ↑, SYP ↑
ROS ↓ 
[144
APP/PS1 mice ♂
6 months old 
CART peptide
IV 0.5 µg/kg 10 days
+ IP 0.5 µg/kg 20 days 
MWM: improved spatial memory Decreased Aβ pathology
Increased insulin signaling 
Soluble Aβ ↓, Aβ enzymes ↓
Akt ↑ 
[145
APP/PS1 mice ♂
8 months old 
CART peptide
IV 0.5 µg/kg 10 days
+ IP 0.5 µg/kg 20 days 
MWM: improved spatial memory Decreased Aβ pathology
Activation of Aβ-degrading enzymes
Decreased reactive oxygen species 
Aβ plaques ↓
NEP, IDE ↑
ROS level ↓ 
[146
Sprague-Dawley rats ♂ Intrahippocampally injected with Aβ1-42
NS age 
CART (55-102)
Intrahippocampal injection
0.02 µg/hemisphere
5 days 
MWM: improved spatial memory
OF: improved locomotor activity 
Decreased Aβ pathology
Attenuated oxidative stress
Decreased neuronal apoptosis 
Aβ plaques, BACE1 ↓
MDA ↓
T-SOD, GSH, ATP, Nrf2, HO-1, NQO1 ↑
Bcl-2 ↑
Bax, caspase 3, caspase 9 ↑ 
[147
 PACAP     
APP(V717I) mice ♂
3 months old 
PACAP38
IN 10 µg/day
5 days/week
3 months 
NOR: improved memory Increased nonamyloidogenic pathway of APP
Increased expression of BDNF 
Neuroprotective sAPPα ↑
soluble Aβ ↓
BDNF ↑ 
[158
 PrRP     
MSG mice ♂
6 months old 
Palm-PrRP31
SC 5 mg/kg
Liraglutide SC 0.2 mg/kg
Daily, 14 days 
 Reduced Tau phosphorylation
Increased insulin signaling 
p-GSK3β(Ser9) ↑
p-Tau Ser396 ↓, p-Tau Thr231 ↓, p-Tau Thr212 ↓
p-PDK1(Ser241) ↑
p-Akt (Thr308), (Ser473) ↑ 
[188
Thy-Tau22 mice ♀
7 months old 
Palm11-PrRP31
Alzet minipumps SC
5 mg/kg/day
2 months 
Y maze: improved short-term working memory Reduced Tau phosphorylation
Increased synaptic plasticity
Increased insulin signaling 
p-GSK3β(Ser9) ↑, PP2A subC ↑
p- Tau Ser396 ↓, p-Tau Ser404 ↓, p-Tau Thr231 ↓
PSD-95 ↑, SYP ↑
p-Akt (Ser473) ↑, p-Akt (Thr308) ↑ 
[189]
[54
APP/PS1 mice ♂
7 months old
APP/PS1 mice ♂
7 months old 
Palm11-PrRP31
SC 5 mg/kg
Liraglutide SC 0.2 mg/kg
Daily, 2 months
Palm11-PrRP31
SC 5 mg/kg
Daily, 2 months 
 Decreased Aβ pathology
Decreased neuroinflammation
Reduced Tau phosphorylation
Mild increase in neurogenesis
Increased synaptogenesis
Reduced Aβ in cerebellum
Reduced microgliosis in cerebellum
Decreased pro-inflammatory proteins in hippocampi
Increased synaptogenesis
Decreased apoptosis 
Aβ plaques ↓
Iba-1 ↓, GFAP ↓
p-Thr231 ↓
DCX ↑
SYP ↑
Aβ plaques ↓
Iba-1 ↓
CD68 ↓, IFNγ ↓
Syntaxin 1A↑, SYP ↑, PSD95 ↑
Bax/Bcl2 ↓ 
[190
 NPFF     
Sprague-Dawley rats ♂
NS age 
NPFF
VTA 1, 2.5, 5, 7.5 or 10 µg/mice 
Cages: reduced locomotion   [225
Wild-type mice (NS strain)
3–4 months old 
NPFF
ICV 1.0 µg/mice
ICV 10 µg/mice 
MWM: spatial acquisition
improved
reduced 
  [226
C57BL/6J mice ♂
3 months old 
1DMe
ICV 1 or 10 nmol 
OL: impaired short-term memory
MWM: impaired long-term memory 
  [227
CFLP mice ♂
NS age 
NPAF
ICV 1.0 µg/mice 
Improved passive
avoidance learning 
  [228
 CRH     
APP/PS1 mice ♂, ♀
1 month old 
R121919 (CRH 1 receptor antagonist)
SC 20 mg/kg
150 days 
MWM: improved spatial memory Decreased Aβ plaque load
Decreased activity of BACE
Increased synaptogenesis 
Aβ plaques ↓
BACE ↓
SYP ↑, MAP2 ↑ 
[244
Tg2576 mice chronically stressed ♂, ♀
4 months 
Antalarmin (CRH 1 receptor antagonist)
20 mg/kg in drinking water, 6 months 
EPM: decreased anxiety-like behavior
Y -maze: improved working memory 
Decreased level of Aβ in chronically stressed mice Aβ plaques ↓, Aβ42 ↓ [245
PS19 mice ♂, stressed for 1 month during the treatment
7 months 
NBI 27914 (CRH 1 receptor antagonist)
SC 10 mg/kg
6 day/week
4 weeks 
Fear conditioning: improved impairment in fear-associated memory Attenuated Tau hyperphosphorylation
Prevented neuronal loss 
AT8 ↓, PHF1 ↓
NeuN ↑ 
[246
Sprague-Dawley rats ♂, ♀ exposed to Isolation-restraint stress
18 months 
R121919 or antalarmin
20 mg/kg mixed in chow diet
3 months 
OF: decreased anxiety
NOR: improved memory
MWM: improved spatial memory 
Increased spine density in cortex
Increased synaptic density 
Spine density ↑
Synaptic density ↑ 
[247

Abbreviations: 1DMe, stable analog of neuropeptide; Aβ, amyloid β; Aif, allograft inflammatory factor 1; APP, amyloid precursor protein; AT8, antibody pTau Ser202&Thr205; BACE1, β-site APP cleaving enzyme 1; Bax, proapoptotic protein; Bcl-2, antiapoptotic protein; BDNF, brain-derived neurotrophic factor; BrdU+, bromouridine positive neurons; CART, cocaine- and amphetamine-regulated transcript; CD68, a scavenger receptor extensively increased in highly reactive microglia; CDK-5, cyclin dependent kinase 5; CRH, corticotropin-releasing hormone; DCX, doublecortin; EPM, elevated plus maze; FF, 3xTg triple transgenic mice; GAD67, glutamic acid decarboxylase 67; GFAP, glial fibrillary acidic protein; GSH, glutathione; GSK-3β, glycogen synthase kinase 3β (pSer9: inhibition, pTyr216: activation); HFD, high-fat diet; HO-1, heme oxygenase-1; Iba1, ionized calcium-binding adaptor molecule 1; Icam1, intercellular adhesion molecule 1; ICV, intracerebroventricular; IDE, insulin-degrading enzyme; IFNγ, interferon γ; IL, interleukin; IN, intranasal; IP, intraperitoneal; IV, intravenous; LTP, long-term potentiation; MAP2, microtubule-associated protein 2; MAPK, mitogen-activated protein kinase; MDA, malondialdehyde; MSG, monosodium glutamate; MSH, melanocyte-stimulating hormone; MWM, Morris water maze; NEP, neprilysin; NeuN neuronal nucleus, marker of mature neurons; NOR, novel object recognition test; NPAF, neuropeptide AF; NPFF, neuropeptide FF; NQO1, NADPH quinone oxidoreductase 1; Nrf2, Nuclear erythroid-2-related factor 2; NS, not specified; OF, open field; OL, object location; PACAP, pituitary adenylate cyclase-activating peptide; PDK1, phosphoinositide-dependent kinase 1; PHF1, antibody pTau Ser396&Ser404; PS1, presenilin 1; PP2A, subC protein phosphatase 2A subunit C; palm, palmitoylated; PrRP, prolactin-releasing peptide; PSD95, postsynaptic density protein 95; ROS, reactive oxygen species; SC, subcutaneous; SYP, synaptophysin; T-SOD, superoxide dismutase; VTA, ventral tegmental area; Zif268, immediate early response gene; ♂, male; ♀, female.

Cocaine- and amphetamine-regulated transcript peptide [CARTp]

In 1995, Douglass et al. [109] discovered that acute administration of cocaine and amphetamine increased the expression of specific mRNAs; thus, they designated this mRNA CART. The structure of CARTp was identified later, in 1998, when Thim et al. [110] described two CARTp isoforms isolated from the rat hypothalamus, CARTp (55-102) and CARTp (61-102); both were subsequently confirmed to be biologically active peptides [111–113]. The newly described CARTp was linked to a previously isolated peptide from the ovine hypothalamus with unknown functions [114]. CARTp is evolutionarily conserved across species; there is 95% amino acid identity between active rat and human CART peptides [109,115,116]. The CARTp receptor has not yet been identified. However, there is evidence suggesting that the CARTp receptor could be a GPCR since CARTp (55-102) can inhibit voltage-dependent Ca2+ channels in primary hippocampal neurons [117]. This inhibitory effect was blocked in cells treated with pertussis toxin, suggesting that CARTp (55-102) mediates this inhibition through the activation of the G proteins Gi/o. CARTp activated extracellular signal-regulated kinase (ERK) in the mouse pituitary tumor cell line AtT20, where specific binding was observed [118,119]. Our group reported the specific binding of CARTp (61-102) in the nanomolar range to rat pheochromocytoma PC12 cells [120]. The number of binding sites is increased fivefold in PC12 cells differentiated to a neuronal phenotype with nerve growth factor (NGF). Our subsequent study demonstrated the activation of the stress-activated protein kinase/c-jun NH2-terminal kinase (SAPK/JNK) pathway in response to CARTp stimulation in PC12 cells [121]. In 2020, Yosten et al. [122] identified the orphan receptor GPR160 as a potential receptor for CARTp, although specific binding of CARTp to GPR160 was not demonstrated in these studies. Our next study did not confirm the presence of GPR160 in PC12 cells [123]. Moreover, no specific binding of CARTp to THP1 cells with high endogenous GPR160 expression or cells transfected with GPR160 was detected. While GPR160 might play a role in CARTp signaling, further studies are needed to identify the receptor for CARTp.

CART is among the most predominant transcripts in the hypothalamus [124], with both CART mRNA and CART immunoreactivity observed in distinct nuclei across the brain, especially in the hypothalamus in the ARC, LHA and PVN, nucleus accumbens, or pituitary, as well as in the periphery, e.g., adrenal glands [125], islets of Langerhans [126] and gut [127]. According to the distribution of CARTp in various brain regions implicated in food intake regulation, it has been proposed that CARTp play a role in the control of eating behavior [125,128]. Since CARTp-deficient mice exhibit late-onset obesity and impaired insulin secretion, these findings were confirmed [129,130]. Subsequent studies of ICV-administered CARTp fragments in rats or mice showed potent food intake-lowering effects, accompanied by the inhibition of NPY neurons [111,131,132]. Moreover, Kristensen et al. demonstrated the importance of leptin in the activation of CART mRNA expression in the ARC. This was supported by the findings of another study in which animals with disrupted leptin signaling were used, which showed almost no expression of the peptide in the brain [133]. The increase in the expression of CARTp after leptin administration [134], the presence of leptin receptors on CART-positive neurons in various regions of the hypothalamus [135], the colocalization of CART with anorexigenic α-MSH in neurons of the ARC [136] and the concomitant modulatory effect of the release of the energy homeostasis regulator TRH from the pituitary [137,138] indicate the effects of CARTp on feeding and energy expenditure. CARTp is also implicated in CCK-induced satiety [139]; moreover, coadministration of CART peptide (ICV) and CCK (IP) synergistically reduced food intake in fasted mice [140]. Six-day-long infusion of CARTp (55-102) into the right lateral cerebral ventricle of DIO rats resulted in a decrease in food intake and body weight loss [141]. In addition to the reduced food intake, the ICV injection of DIO rats with CARTp (55-102) showed enhanced lipid metabolism, as indicated by increased plasma levels of nonesterified fatty acids, suggesting the hydrolysis of stored triglycerides [142].

The first indications of the potential neuroprotective effects of CARTp were described in 2011, when ICV injection of CARTp for four consecutive days in rats resulted in significantly improved spatial learning and memory in the MWM test [143]. Furthermore, immunohistochemical data have shown significantly increased CART-immunoreactivity in brain areas involved in learning and memory in rats after four days of training in the MWM test [143]. The neuroprotective effects of CARTp on the pathology of AD were studied by Xu et al. They observed Aβ plaque-associated CART immunoreactivity in the hippocampus and cortex of 8-month-old APP/PS1 mice as well as in the cortex of human AD patients [144]. Chronic CARTp treatment attenuated memory deficits in APP/PS1 mice and improved synaptic ultrastructure and long-term potentiation of neurons. Additionally, it reduced reactive oxygen species but did not have an impact on the reduction in Aβ [144]. A subsequent study showed significantly decreased levels of soluble Aβ1-40 and Aβ1-42 in the hippocampus of APP/PS1 mice after CARTp treatment [145]. The number of Aβ plaques was reduced due to activation of Aβ-degrading enzymes such as neprilysin, insulin-degrading enzyme, and low-density lipoprotein receptor-related protein 1 [146]. Moreover, CARTp reduced levels of reactive oxygen species in the hippocampus of APP/PS1 [146]. Similar results were observed in rats injected intrahippocampally with Aβ1-42; Aβ induced a reduction in CART-immunoreactive fibers, but this was prevented by 5-day pretreatment with CARTp injected to the hippocampus [147]. CARTp further improved spatial memory in MWM, decreased oxidative stress and attenuated neuronal apoptosis [147].

Taken together, these findings suggest that CARTp could be used as an antiobesity or neuroprotective drug in the treatment of neurodegenerative diseases. Its beneficial effects on mouse models of obesity and AD-like pathology are summarized in Tables 1 and 2. However, understanding the exact mechanism of action of CARTp in models of obesity and neurodegeneration is necessary, and discovering of the CARTp receptor is essential for this purpose.

Pituitary adenylate cyclase-activating peptide (PACAP)

PACAP is a 38-amino-acid or 27-amino-acid neuropeptide produced and released both in the periphery and the CNS, especially in the VMN, or in the LHA and PVN in the hypothalamus [148–150]. PACAP binds to three GPCRs: PAC1R, VPAC1, and VPAC2 [151]. Its metabolic pathways are linked to the regulation of body weight and the development of obesity and metabolic syndrome. In addition to appetite regulation, PACAP also increased thermogenesis in mice [22,23]. The importance of PACAP is stressed by its involvement in the leptin-induced decrease in food intake and increased thermogenesis as a marker of increased energy expenditure [152]. Moreover, PACAP stimulates POMC neurons in the ARC but inhibits NPY/AgRP [153]. A study of PACAP-null mice revealed decreased survival of newborn mice when the mice were housed at room temperature. Moreover, these mice had decreased body weight compared to that of their wild-type littermates due to a decreased amount of WAT [154]. Even though PACAP is involved in the regulation of energy homeostasis and could be considered a possible target for obesity treatment, the direct antiobesity effects of PACAP have still not been well explored [155].

High expression of PACAP was detected in the hippocampus, particularly in the dentate gyrus (DG), where increased synaptic transmission was observed after PACAP treatment [156]. This finding highlights the possible neuroprotective effects of PACAP in the treatment of dementia. Postmortem analysis of brains from patients with AD revealed a negative correlation between the level of Aβ plaques and PACAP, and between the level of PACAP and tau pathology (according to Braak stages of AD severity) [157]. As summarized in Table 2, 3-month-long intranasal application of PACAP to APP(V717I) mice harboring the London mutation improved short-term memory in the novel object recognition test, decreased the level of soluble Aβ, and increased the levels of neurotrophin BDNF [158].

Prolactin-releasing peptide (PrRP)

PrRP is a hypothalamic neuropeptide with a misleading name [159]. Shortly after its discovery, the initially described stimulation of prolactin was questioned; nevertheless, the name remained [160,161]. In organism, two equally active isoforms can be found: PrRP31 with 31 amino acids, or its shorter analog PrRP20 with an identical C-terminal sequence. The last two amino acids at the C-terminus, Arg-Phe-amide, are important for preserving the binding affinity of PrRP to its receptor and proper biological activity [159,162–164]. PrRP was identified as a ligand of GPR10 (also known as hGR3 or UHR1) [159]. It displayed high affinity for the receptor type 2 for neuropeptide FF (NPFFR2), which is another neuropeptide from the RF-amide family [165]. Studies investigating the distribution of PrRP or its receptor in the organism revealed high expression of PrRP in centers implicated in food intake regulation, such as the hypothalamus (DMN, VMH, or PVN) or in the NTS in the brainstem [24,166–169]. Subsequent studies confirmed that ICV injection of PrRP significantly reduced food intake in free-fed rats and decreased body weight [24,164,170]. The weight loss observed was greater than that corresponding to a reduction in food intake alone, suggesting that increased energy expenditure also contributes to the weight loss induced by PrRP administration [171]. The importance of PrRP in food intake regulation and energy balance is emphasized by the fact that PrRP expression is directly stimulated by leptin, the main regulator of energy homeostasis [172]. PrRP also mediates the anorexigenic effect of peripheral anorexigenic CCK [173]. Moreover, PrRP-deficient [174] or GPR10-deficient [175,176] mice develop late-onset obesity and decreased energy expenditure.

The peripheral injection of natural PrRP31, a convenient route for potential anti-obesity treatment, does not decrease food intake in fasted mice [177]. Thus, a series of PrRP20 or PrRP31 lipidized with fatty acids of different lengths (from octanoyl to stearoyl [stear]) at the N-terminus were designed. Lipidization did not influence binding to the GPR10 receptor; moreover, these analogs exhibited increased affinity for NPFFR2 [177]. Only myr-PrRP20, myr-PrRP31, palm-PrRP31 and stear-PrRP31 significantly reduced food intake in overnight fasted mice after acute subcutaneous (SC) application [177]. In free-fed rats, palm-PrRP31 administered for three consecutive days significantly reduced food intake after SC or intraperitoneal (IP) injection at a dose of 5 mg/kg. A comparable effect was observed after intravenous (IV) administration even at a dose of 0.1 mg/kg [178]. Finally, myr-PrRP20 or palm-PrRP31 was chronically SC injected into DIO mice for 2 weeks; this treatment resulted in significant weight loss and improved metabolic parameters related to obesity, such as decreased leptin or insulin levels [177]. A comprehensive study of different lipidized analogs of PrRP31 performed by Pražienková et al. [179] defined an analog of PrRP31 palmitoylated at position 11 (where arginine is substituted with lysine) through a γ-glutamic acid linker (palm11-PrRP31) as an analog with improved bioavailability. Two-week-long treatment of DIO mice significantly reduced body weight, improved metabolic parameters, and decreased de novo lipogenesis. Both analogs also increased the expression of uncoupling protein 1 in brown adipose tissue (BAT), suggesting increased energy expenditure in these mice [177,179]. A subsequent study of chronic SC administration of palm11-PrRP31 investigated the possible yo-yo effect after termination of the treatment [180]. One group of DIO mice was SC injected for 28 days with palm11-PrRP, while the second group received palm11-PrRP31 for 14 days and then saline for the subsequent 14 days. As expected, 28 days of treatment significantly reduced the body weight of the mice. A comparable body-weight reduction was observed in the palm11-PrRP31-saline group after 2 weeks of treatment. Interestingly, there was no body weight gain within the subsequent 2 weeks of saline administration [180]. Similar trends toward a reduction in food intake, decreased body weight, and improvements in metabolic parameters, such as decreased levels of glucose, leptin, or insulin, were observed in several rat DIO models [181–183]. The effects of palmitoylated-PrRP31 analogs in different models of obesity were reviewed by Mráziková et al. [184]. Another series of modified PrRP analogs with multiple ethylene glycol-fatty acid (MEG-FA) stapling platform was described by Pflimlin et al. [185]. The lead compound 18-S4, a selective agonist of GPR10, showed improved bioavailability and stability in serum. Twelve-day-long SC treatment of DIO mice resulted in a significant decrease in body weight [185]. On the other hand, several studies have described the importance of dual agonism toward GPR10 and NPFFR2 for the full antiobesity effect of lipidized PrRP31 analogs [177,179,186,187]. Alexopoulou et al. designed different series of lipidized PrRP analogs with selectivity for either GPR10 or both GPR10 and NPFFR2. Only analogs with dual agonist effect had potent antiobesity effects. Moreover, body weight did not increase after termination of treatment [187].

Palm-PrRP31 also significantly decreased the body weight of mice with obesity induced by monosodium glutamate (MSG), which is repeatedly SC injected to newborn mice [188]. In addition to obesity, MSG-obese mice with pre-diabetes, leptin and insulin resistance exhibited central insulin resistance leading to increased hippocampal Tau hyperphosphorylation. This effect was attenuated by palm-PrRP31 treatment through the activation of the central insulin signaling cascade and inhibition of glycogen-synthase kinase 3β (GSK-3β), the main kinase of the Tau protein [188]. The effect of palm11-PrRP31 on the attenuation of Tau hyperphosphorylation was further observed in Thy-Tau22 mice overexpressing mutated human Tau with accelerated hyperphosphorylation [189]. One month of SC infusion of palm11-PrRP31 attenuated Tau hyperphosphorylation at different epitopes in the hippocampus, increased the expression of markers of synaptic plasticity, and improved spatial working memory in the Y-maze test [189]. Potential neuroprotective effects of palm11-PrRP31 were also demonstrated in APP/PS1 mice, in which 2 months of treatment significantly decreased the number of Aβ plaques in the hippocampus, cortex [54], and cerebellum [190]. Tau phosphorylation at different epitopes was also attenuated after palm11-PrRP31 treatment in the hippocampus [54]. Aβ plaques colocalize with microgliosis and astrocytosis, whose levels also decrease after treatment with palm11-PrRP31 [54,190]. Further analysis revealed changes in the distribution of various lipids, mainly gangliosides (GM2 36:1, GM3 36:1) and phosphatidylinositols (PI 38:4, 36:4), around Aβ plaques; moreover, the lipid profile normalized after treatment with palm11-PrRP31 [191]. Moreover, palm11-PrRP31 increased synaptic plasticity [54,190], neurogenesis manifested as an increase in doublecortin-positive cells in the hippocampal DG [54], and decreased apoptosis in the hippocampus [190]. Recently, a beneficial effect on adult neurogenesis, which was impaired in DIO mice, was described [192]. The possible implication of PrRP and GPR10 for proper brain function was stressed by the recent finding that decreased GPR10 receptor levels were observed in patients with AD [193].

Studies in mouse models of obesity (summarized in Table 1) or mouse models of amyloidosis or tauopathy (summarized in Table 2) have shown promising potential antiobesity and neuroprotective properties of palmitoylated PrRP31 analogs.

Neuropeptide FF (NPFF)

The octapeptide NPFF and the octadecapeptide neuropeptide AF (NPAF) were first isolated from bovine brain tissue in 1985 [194]. In rodents, NPFF was found to be highly expressed in the brainstem in the NTS, dorsal horn of the spinal cord, and hypothalamus between the DMN and VMN, with neuronal projections to the PVN [195–198]. Autoradiographic studies have shown that NPFF receptors are present in memory-related brain regions, such as the amygdala, hippocampus, bed nucleus of the stria terminalis, and cortical regions [199,200].

The function of NPFF is associated with two types of GPCRs–NPFFR1 and the NPFFR2 receptor [200]. The presence of the NPFFR1 and NPFFR2 mRNAs in the medulla, lateral hypothalamus, and thalamus indicates that NPFF participates in the regulation of responses to painful stimuli [200,201]. ICV administration of NPFF to mice reduced the analgesic effects of morphine and lowered the pain threshold, indicating that NPFF likely has anti-opioid effects. This is further supported by the fact that ICV administration of the anti-NPFF antiserum increased opiate-induced analgesia and restored sensitivity to morphine in mice that had already developed tolerance to its analgesic effects [202]. NPFF was found to be physiologically more active than NPAF in decreasing tail-flick latency in rats and it also attenuated the prolongation of tail-flick latency induced by morphine [194].

Multiple NPFF agonists and antagonists resistant to peptidases, which cause rapid inactivation of NPFF, were synthesized and tested. The analog 1DMe ([D-Tyr1, (N-Me)-Phe4] NPFF) has an affinity comparable to that of NPFF [203] and has been shown to inhibit morphine-induced analgesia in mice [204]. Several candidates for NPFF receptor agonists and antagonists have been synthesized, but no antagonist has demonstrated high selectivity and activity [205]. Centrally administered RF9, a reported NPFF receptors antagonist, was found to block hyperalgesia after prolonged administration of opioids [206] and antagonize the hypothermic effects induced by the selective agonists of NPFFR1 and NPFFR2 in mice [207]. However, RF9 did not reverse the anorectic effect of the agonist [Tyr1]NPFF, and its biological effects appear to be more agonistic than antagonistic [208].

Since many opioid agonists have been shown to increase food intake, NPFF was also investigated in this context. ICV administration of NPFF rapidly reduced food intake in dose-dependent manner in fasted rats [209,210]. This anorexigenic effect was initially attributed to increased water intake [210]; however, in other studies, this dipsogenic effect was no longer reported [211]. The regulation of feeding is likely through modulation of hypothalamic neurons [212]. Furthermore, both the central administration of NPFF [213] or NPAF [214] reduced food intake in fasted chicks. The centrally injected agonist [Tyr1]NPFF significantly lowered food intake in fasted mice [215]. Interestingly, ICV administration of NPFF caused a significant decrease in food intake in both wild-type mice and mice lacking GPR10 receptor. The ability of NPFF to reduce food intake in the GPR10 KO mice suggests that NPFFR2 expression is maintained in these animals [173]. NPFF was reported to promote the activation of adipose tissue macrophages (ATMs), which have an impact on the development of obesity-induced metabolic diseases, to an alternative M2 activation state, which is metabolically beneficial and is activated in lean adipose tissue. In ATMs, NPFFR2 is expressed in both humans and mice. Plasma levels of NPFF are decreased in obese patients and mice on a HFD and restored after caloric restriction. In this study, HFD-fed mice treated IP with NPFF did not decrease body weight, food intake, or the weight of adipose tissue [216]. In our recent study, involving lipidized NPFF and NPAF analogs, we observed only a slight anorexigenic effect on fasted lean mice following the SC administration of octanoylated-1DMe analog. In mice fed a HFD, long-term treatment did not result in reduced food intake or body weight [217]. Alongside its anorexigenic effect, NPFF was implicated in blood pressure regulation [218,219] as well as body temperature [220,221].

Multiple experiments suggest a role for NPFF in cognitive functions due to its opioid-modulating properties, as the endogenous opioid system is involved in the modulation of behavior. A single ICV injection of NPFF reduced the expression of morphine-induced sensitization in rats with a conditioned place preference [222], as did the rewarding effects of cocaine or amphetamine [223,224]. NPFF also inhibited hyperlocomotor activity of cocaine-induced sensitization in mice [223]. RF9 reversed the inhibitory effect of NPFF but did not affect amphetamine- or saline-conditioned rats [224].

Injection of NPFF in the ventral tegmental area reduced the increase in locomotor activity induced by novelty exposure [225]. Moreover, NPFF impairs spatial acquisition by significantly reducing spatial learning in the MWM [226]. 1DMe, injected via the ICV, induced delayed hyperlocomotion and mildly impaired both short-term and long-term spatial memory without affecting contextual fear memory in mice [227]. Additionally, the NPAF has a stimulatory effect on memory consolidation in passive avoidance learning [228]. Serum NPFF levels are significantly elevated in patients with spinal cord injury [229], which is associated with cognitive impairment [230]. These data suggest that the NPFF may have prognostic value for predicting cognitive impairment in patients with spinal cord injury, as its peripheral levels are normally limited and could arise due to leakage from CNS tissues [231].

Taken together, these results demonstrate the small but complex influence of the NPFF system on mouse behavior and cognitive functions, as summarized in Table 2. However, only a limited number of studies have been conducted in this area, and further experiments need to be explored.

Corticotropin-releasing hormone (CRH)

The hypothalamic CRH is an important physiological activator of POMC-derived hormones, such as ACTH and β-endorphins [232–234]. CRH consists of 41 amino acids, has an amidated C-terminus, is widely distributed in the CNS [235], for example, in the hypothalamus in the PVN with projections to the ME, in the cortex or in the hippocampus. CRH signals through two receptors, CRH-R1 and CRH-R2, both belonging to the GPCR family and widely distributed in both the CNS and the periphery [236].

CRH is considered an anorexigenic compound. However, its direct involvement in obesity treatment in preclinical models has not yet been proven. When administered via the ICV, CRH significantly decreased food intake in rats [237] and rhesus monkeys [238], after acute administration. Seven-day-long infusion of CRH resulted in significantly reduced food intake in rats followed by decreased body weight and increased thermogenesis in BAT [237].

Early dysregulation of the hypothalamic–pituitary–adrenal (HPA) axis or stress axis was observed in patients with sporadic AD, followed by increased secretion of glucocorticoids. Hormones of the HPA axis and their receptors are proposed to be involved in AD; therefore, they could be targets for treating neurodegenerative diseases (reviewed previously [239]). Intrahippocampal CRH administration to mice exposed to acute stress via the food shock test or via an environment with predator odor increased hippocampal long-term potentiation and strengthened synaptic plasticity. Thus, CRH could be implicated in stress-enhanced memory consolidation during stress conditions [240]. In patients with AD, a reduced level of CRH was observed [241], whereas the number of CRH receptors increased [242]. In AD brain tissues, reduced concentrations of CRF-like immunoreactivity are accompanied by a significant reciprocal increase in CRF receptor binding within affected cortical areas. This increase in CRH binding correlates significantly with the decreased levels of CRH [243].

Further research on this phenomenon revealed that in different mouse models of AD, for example, in APP/PS1 mice [244], Tg2576 mice [245], and PS19 mice, a model of tauopathy [246], antagonists of CRH receptor 1 (CRH-R1) improved memory deficits and decreased Aβ and Tau hyperphosphorylation. Moreover, a CRH-R1 antagonist also prevents memory deficits and synaptic loss in 18-month-old rats with stress-induced memory deficits [247].

Hormones of the HPA axis and their receptors are proposed to be involved in AD; therefore, they could be targets for treating the neurodegenerative diseases reviewed previously [239], and are summarized in Table 2.

Thyrotropin-releasing hormone (TRH)

The hypothalamic tripeptide TRH (pGlu-His-Pro-NH2) expressed in the PVN [248] is directly stimulated by leptin [249] or POMC-derived peptides [250], and inhibited by NPY/AgRP [251]. TRH is synthesized from a larger inactive precursor pro-TRH through a series of post-translational modifications [252]. This hormone exerts its effects through GPCR receptors, which are categorized as TRH-R1, TRH-R2, and TRH-R3. They exhibit species-specific variations; in humans, TRH-R1 is the unique type, while rodents express a second subtype, TRH-R2 and birds express TRH-R3 together with TRH-R1 [253].

TRH is known as the primary regulator of the hypothalamic-pituitary-thyroid axis, which is important for maintaining energy expenditure and body weight and is active even in states of leptin resistance associated with obesity [254]. Moreover, in a state of negative energy balance, the levels of TRH decrease [255,256]. Conversely, in DIO rats, the level of TRH was significantly increased [254]. Different routes of TRH application (IV, ICV, and SC) resulted in significantly reduced food intake and increased body temperature [25,257,258]. It has been described that TRH inhibits both food and water intake [259]. For example, the short-term reduction, with no concurrent reduction in body weight, occurs in rats following SC administration of TRH at dark onset [25]. Additionally, in another study, TRH decreased water intake when injected ICV [260]. However, in long-term treatment, with TRH administered twice daily for 5 days, it was observed that TRH did not reduce food intake, but instead, it increased water intake [25]. The reason for the stimulated water consumption is not clear. TRH administered both ICV and parenterally suppressed stress-induced eating. This effect was partially reversed by ICV administration of the long-acting synthetic enkephalin analog, suggesting that TRH and endogenous opiates may have a mutually antagonistic effect on ingestive behavior [261]. As shown in Table 1, chronic IP application of TRH to DIO mice reduced food intake and body weight, and improved metabolic parameters related to obesity, such as decreased levels of leptin, triglycerides, or cholesterol [262].

The role of TRH in AD is not well known; however, compared with healthy elderly controls, AD patients were shown to have decreased levels of TRH in the hippocampus [263]. A peptide analog of TRH, MK-771, improved spatial memory in a rat model of AD with medial septal lesions [264]. Moreover TRH could be implicated in the increased excitability of hippocampal CA1 neurons [265]. On the other hand, in a model of early-stage AD induced by intrahippocampal injection of okadaic acid, which enhances the activity of the Tau kinase GSK-3β and increases Tau phosphorylation, the level of TRH increases in the brain, as does the level of TRH in the blood serum [266].

The use of anorexigenic neuropeptides for obesity or neurodegeneration treatment is still under investigation. Potential therapies targeting hypothalamic neuropeptide systems are in intensive preclinical research and have shown promising results for weight reduction, improvement of metabolic parameters, and amelioration of the loss of memory, neuroinflammation, or neurogenesis associated with neurodegenerative diseases.

While the hypothalamic ARC is not entirely isolated from the peripheral circulation, targeting central neuropeptide systems in other CNS regions requires overcoming the blood–brain barrier. This often requires high drug doses, elevating the risk of possible side effects. Therefore, anorexigenic neuropeptides and their peptide-based analogs pose challenges when administered through injectable options. To achieve a central biological effect on their receptors after peripheral administration, it is necessary to modify neuropeptides to enhance their stability and bioavailability. In this review, we showed that anorexigenic neuropeptides, such as melanocortins, CARTp, PrRP, NPFF, PACAP, CRH and THR and their analogs not only decrease body weight, lower blood glucose levels, or ameliorate lipid profiles, but also improve cognitive impairment and the hallmarks of AD-like pathology in preclinical models (Figure 2).

Scheme of beneficial effects of anorexigenic neuropeptides or their modified analogs in the treatment of obesity and neurodegeneration

Figure 2
Scheme of beneficial effects of anorexigenic neuropeptides or their modified analogs in the treatment of obesity and neurodegeneration

Administration of anorexigenic neuropeptides or their modified analogs reduces food intake, resulting in weight loss and decreased white adipose tissue, known for pro-inflammatory cytokine secretion. This treatment further mitigates neuroinflammation, characterized by microgliosis, and astrocytosis, lowers levels of amyloid-β (Aβ), and diminishes neurofibrillary tangles formed by hyperphosphorylated Tau protein in the brain. Additionally, it promotes synaptogenesis and neurogenesis, leading to improved learning and memory.

BBB: blood brain barrier.

Figure 2
Scheme of beneficial effects of anorexigenic neuropeptides or their modified analogs in the treatment of obesity and neurodegeneration

Administration of anorexigenic neuropeptides or their modified analogs reduces food intake, resulting in weight loss and decreased white adipose tissue, known for pro-inflammatory cytokine secretion. This treatment further mitigates neuroinflammation, characterized by microgliosis, and astrocytosis, lowers levels of amyloid-β (Aβ), and diminishes neurofibrillary tangles formed by hyperphosphorylated Tau protein in the brain. Additionally, it promotes synaptogenesis and neurogenesis, leading to improved learning and memory.

BBB: blood brain barrier.

Close modal

Anorexigenic neuropeptides hold promise for addressing both obesity and neurodegeneration by modulating food intake, energy homeostasis, and displaying neuroprotective properties. Despite this potential, translating these discoveries into clinical practice presents significant challenges, including issues related to central nervous system access, side effects, and efficacy. These neuropeptides offer a promising avenue for developing neuropeptide receptor ligands with diverse pharmacological properties, and several analogs of anorexigenic peptides are currently undergoing preclinical trials. However, several obstacles persist, such as limited delivery to the brain and the need for comprehensive evaluation of their physiological effects, which may complicate their use in clinical trials. Nevertheless, they represent a valuable resource for developing novel pharmacological tools and therapeutic leads in both health and disease. However, targeting neuropeptides remains challenging due to the site of action and the route of administration.

The authors declare that there are no competing interests associated with the manuscript.

The study was supported by National Institute for Research of Metabolic and Cardiovascular Diseases (Programme EXCELES, ID Project No. LX22NPO5104) – Funded by the European Union – Next Generation EU, by the Technology Agency of the Czech Republic, National center of competence – Personalized Medicine – Diagnostics and Therapy [grant number TN02000109], and Czech Academy of Sciences RVO: 61388963 and RVO: 67985823.

V. Strnadová: Conceptualization, Methodology, Writing—original draft, Writing—review & editing. A. Pačesová: Conceptualization, Supervision, Methodology, Writing—original draft, Writing—review & editing. V. Charvát: Investigation, Writing—original draft, Writing—review & editing. Z. Šmotková: Data curation, Writing—original draft, Writing—review & editing. B. Železná: Writing—review & editing. J. Kuneš: Funding acquisition, Writing—original draft, Writing—review & editing. L. Maletínská: Conceptualization, Supervision, Funding acquisition, Writing—original draft, Writing—review & editing.

AD

Alzheimer’s disease

AgRP

agouti-related peptide

ARC

arcuate nucleus

BAT

brown adipose tissue

CART

cocaine- and amphetamine-regulated transcript

CNS

central nervous system

ERK

extracellular signal-regulated kinase

GPAP

glial fibrillary acidic protein

HPA

hypothalamic–pituitary–adrenal

IL

interleukin

ME

media eminence

MEG-FA

multiple ethylene glycol-fatty acid

NPAF

neuropeptide AF

NPFF

neuropeptide FF

NPY

neuropeptide Y

PACAP

pituitary adenylate cyclase-activating peptide

POMC

pro-opiomelanocortin

PrRP

prolactin-releasing peptide

TRH

thyrotropin-releasing hormone

WAT

white adipose tissue

1.
Guyenet
S.J.
and
Schwartz
M.W.
(
2012
)
Clinical review: Regulation of food intake, energy balance, and body fat mass: implications for the pathogenesis and treatment of obesity
.
J. Clin. Endocrinol. Metab.
97
,
745
755
[PubMed]
2.
Sobrino Crespo
C.
,
Perianes Cachero
A.
,
Puebla Jimenez
L.
,
Barrios
V.
and
Arilla Ferreiro
E.
(
2014
)
Peptides and food intake
.
Front. Endocrinol.
5
,
58
[PubMed]
3.
Joly-Amado
A.
,
Cansell
C.
,
Denis
R.G.
,
Delbes
A.S.
,
Castel
J.
,
Martinez
S.
et al.
(
2014
)
The hypothalamic arcuate nucleus and the control of peripheral substrates
.
Best Pract. Res. Clin. Endocrinol. Metab.
28
,
725
737
[PubMed]
4.
Clayton
R.W.
,
Lovell-Badge
R.
and
Galichet
C.
(
2022
)
The properties and functions of glial cell types of the hypothalamic median eminence
.
Front Endocrinol. (Lausanne)
13
,
953995
[PubMed]
5.
Jais
A.
and
Bruning
J.C.
(
2022
)
Arcuate nucleus-dependent regulation of metabolism-pathways to obesity and diabetes mellitus
.
Endocr. Rev.
43
,
314
328
[PubMed]
6.
Friedman
J.M.
and
Halaas
J.L.
(
1998
)
Leptin and the regulation of body weight in mammals
.
Nature
395
,
763
770
[PubMed]
7.
Frederich
R.C.
,
Hamann
A.
,
Anderson
S.
,
Lollmann
B.
,
Lowell
B.B.
and
Flier
J.S.
(
1995
)
Leptin levels reflect body lipid content in mice: evidence for diet-induced resistance to leptin action
.
Nat. Med.
1
,
1311
1314
[PubMed]
8.
Perez-Leighton
C.
,
Kerr
B.
,
Scherer
P.E.
,
Baudrand
R.
and
Cortes
V.
(
2023
)
The interplay between leptin, glucocorticoids, and GLP1 regulates food intake and feeding behaviour
.
Biol. Rev. Camb. Philos. Soc.
[PubMed]
9.
Harris
R.B.
(
2014
)
Direct and indirect effects of leptin on adipocyte metabolism
.
Biochim. Biophys. Acta
1842
,
414
423
[PubMed]
10.
Kojima
M.
,
Hosoda
H.
,
Date
Y.
,
Nakazato
M.
,
Matsuo
H.
and
Kangawa
K.
(
1999
)
Ghrelin is a growth-hormone-releasing acylated peptide from stomach
.
Nature
402
,
656
660
[PubMed]
11.
Lutz
T.A.
(
2009
)
Control of food intake and energy expenditure by amylin-therapeutic implications
.
Int. J. Obes.
33
,
S24
S27
12.
Cawthon
C.R.
and
de La Serre
C.B.
(
2021
)
The critical role of CCK in the regulation of food intake and diet-induced obesity
.
Peptides
138
,
170492
[PubMed]
13.
Muller
T.D.
,
Finan
B.
,
Bloom
S.R.
,
D'Alessio
D.
,
Drucker
D.J.
,
Flatt
P.R.
et al.
(
2019
)
Glucagon-like peptide 1 (GLP-1)
.
Mol. Metab.
30
,
72
130
[PubMed]
14.
Karra
E.
,
Chandarana
K.
and
Batterham
R.L.
(
2009
)
The role of peptide YY in appetite regulation and obesity
.
J. Physiol.
587
,
19
25
[PubMed]
15.
Cummings
D.E.
and
Overduin
J.
(
2007
)
Gastrointestinal regulation of food intake
.
J. Clin. Invest.
117
,
13
23
[PubMed]
16.
Valassi
E.
,
Scacchi
M.
and
Cavagnini
F.
(
2008
)
Neuroendocrine control of food intake
.
Nutr. Metab. Cardiovasc. Dis.
18
,
158
168
[PubMed]
17.
Lenard
N.R.
and
Berthoud
H.R.
(
2008
)
Central and peripheral regulation of food intake and physical activity: pathways and genes
.
Obesity (Silver Spring)
16
,
S11
S22
[PubMed]
18.
Vrontakis
M.E.
(
2002
)
Galanin: a biologically active peptide
.
Curr. Drug Targets CNS Neurol. Disord.
1
,
531
541
[PubMed]
19.
Qu
D.
,
Ludwig
D.S.
,
Gammeltoft
S.
,
Piper
M.
,
Pelleymounter
M.A.
,
Cullen
M.J.
et al.
(
1996
)
A role for melanin-concentrating hormone in the central regulation of feeding behaviour
.
Nature
380
,
243
247
[PubMed]
20.
Rodgers
R.J.
,
Ishii
Y.
,
Halford
J.C.
and
Blundell
J.E.
(
2002
)
Orexins and appetite regulation
.
Neuropeptides
36
,
303
325
[PubMed]
21.
Mastorakos
G.
and
Zapanti
E.
(
2004
)
The hypothalamic-pituitary-adrenal axis in the neuroendocrine regulation of food intake and obesity: the role of corticotropin releasing hormone
.
Nutr. Neurosci.
7
,
271
280
[PubMed]
22.
Bozadjieva-Kramer
N.
,
Ross
R.A.
,
Johnson
D.Q.
,
Fenselau
H.
,
Haggerty
D.L.
,
Atwood
B.
et al.
(
2021
)
The role of mediobasal hypothalamic PACAP in the control of body weight and metabolism
.
Endocrinology
162
,
23.
Morley
J.E.
,
Horowitz
M.
,
Morley
P.M.
and
Flood
J.F.
(
1992
)
Pituitary adenylate cyclase activating polypeptide (PACAP) reduces food intake in mice
.
Peptides
13
,
1133
1135
[PubMed]
24.
Lawrence
C.B.
,
Celsi
F.
,
Brennand
J.
and
Luckman
S.M.
(
2000
)
Alternative role for prolactin-releasing peptide in the regulation of food intake
.
Nat. Neurosci.
3
,
645
646
[PubMed]
25.
Choi
Y.H.
,
Hartzell
D.
,
Azain
M.J.
and
Baile
C.A.
(
2002
)
TRH decreases food intake and increases water intake and body temperature in rats
.
Physiol. Behav.
77
,
1
4
[PubMed]
26.
Arora
S.
and
Anubhuti
(
2006
)
Role of neuropeptides in appetite regulation and obesity–a review
.
Neuropeptides
40
,
375
401
[PubMed]
27.
Yu
J.H.
and
Kim
M.S.
(
2012
)
Molecular mechanisms of appetite regulation
.
Diabetes Metab. J.
36
,
391
398
[PubMed]
28.
Kennedy
G.C.
(
1953
)
The role of depot fat in the hypothalamic control of food intake in the rat
.
Proc. R. Soc. Lond. B Biol. Sci.
140
,
578
596
[PubMed]
29.
Vaneckova
I.
,
Maletinska
L.
,
Behuliak
M.
,
Nagelova
V.
,
Zicha
J.
and
Kunes
J.
(
2014
)
Obesity-related hypertension: possible pathophysiological mechanisms
.
J. Endocrinol.
223
,
R63
R78
[PubMed]
30.
Kloock
S.
,
Ziegler
C.G.
and
Dischinger
U.
(
2023
)
Obesity and its comorbidities, current treatment options and future perspectives: challenging bariatric surgery?
Pharmacol. Ther.
251
,
108549
[PubMed]
31.
Alford
S.
,
Patel
D.
,
Perakakis
N.
and
Mantzoros
C.S.
(
2018
)
Obesity as a risk factor for Alzheimer's disease: weighing the evidence
.
Obes. Rev.
19
,
269
280
[PubMed]
32.
Rahman
M.M.
,
Islam
M.R.
,
Supti
F.A.
,
Dhar
P.S.
,
Shohag
S.
,
Ferdous
J.
et al.
(
2023
)
Exploring the therapeutic effect of neurotrophins and neuropeptides in neurodegenerative diseases: at a glance
.
Mol. Neurobiol.
60
,
4206
4231
[PubMed]
33.
Pini
L.
,
Pievani
M.
,
Bocchetta
M.
,
Altomare
D.
,
Bosco
P.
,
Cavedo
E.
et al.
(
2016
)
Brain atrophy in Alzheimer's disease and aging
.
Ageing Res. Rev.
30
,
25
48
[PubMed]
34.
Ball
M.J.
(
1977
)
Neuronal loss, neurofibrillary tangles and granulovacuolar degeneration in the hippocampus with ageing and dementia. A quantitative study
.
Acta Neuropathol. (Berl)
37
,
111
118
35.
WHO
(
2016
)
Dementia
.
[cited 2024 30.01.]. Available from: http://www.who.int/mediacentre/factsheets/fs362/en/
36.
Serrano-Pozo
A.
,
Frosch
M.P.
,
Masliah
E.
and
Hyman
B.T.
(
2011
)
Neuropathological alterations in Alzheimer disease
.
Cold Spring Harb Perspect Med.
1
,
a006189
[PubMed]
37.
Flores-Cordero
J.A.
,
Perez-Perez
A.
,
Jimenez-Cortegana
C.
,
Alba
G.
,
Flores-Barragan
A.
and
Sanchez-Margalet
V.
(
2022
)
Obesity as a risk factor for dementia and Alzheimer's disease: the role of leptin
.
Int. J. Mol. Sci.
23
,
[PubMed]
38.
Liu
Y.
,
Liu
F.
,
Grundke-Iqbal
I.
,
Iqbal
K.
and
Gong
C.X.
(
2011
)
Deficient brain insulin signalling pathway in Alzheimer's disease and diabetes
.
J. Pathol.
225
,
54
62
[PubMed]
39.
Kacirova
M.
,
Zmeskalova
A.
,
Korinkova
L.
,
Zelezna
B.
,
Kunes
J.
and
Maletinska
L.
(
2020
)
Inflammation: major denominator of obesity, Type 2 diabetes and Alzheimer's disease-like pathology?
Clin. Sci. (Lond.)
134
,
547
570
[PubMed]
40.
Nunomura
A.
and
Perry
G.
(
2020
)
RNA and oxidative stress in Alzheimer's disease: focus on microRNAs
.
Oxid. Med. Cell Longev.
2020
,
2638130
[PubMed]
41.
Launer
L.J.
(
2002
)
Demonstrating the case that AD is a vascular disease: epidemiologic evidence
.
Ageing Res. Rev.
1
,
61
77
[PubMed]
42.
Lopez-Gambero
A.J.
,
Rosell-Valle
C.
,
Medina-Vera
D.
,
Navarro
J.A.
,
Vargas
A.
,
Rivera
P.
et al.
(
2021
)
A negative energy balance is associated with metabolic dysfunctions in the hypothalamus of a humanized preclinical model of Alzheimer's disease, the 5XFAD mouse
.
Int. J. Mol. Sci.
22
,
43.
Akter
K.
,
Lanza
E.A.
,
Martin
S.A.
,
Myronyuk
N.
,
Rua
M.
and
Raffa
R.B.
(
2011
)
Diabetes mellitus and Alzheimer's disease: shared pathology and treatment?
Br. J. Clin. Pharmacol.
71
,
365
376
[PubMed]
44.
Vanhanen
M.
,
Koivisto
K.
,
Moilanen
L.
,
Helkala
E.L.
,
Hanninen
T.
,
Soininen
H.
et al.
(
2006
)
Association of metabolic syndrome with Alzheimer disease: a population-based study
.
Neurology
67
,
843
847
[PubMed]
45.
Basaranoglu
M.
and
Neuschwander-Tetri
B.A.
(
2006
)
Nonalcoholic fatty liver disease: clinical features and pathogenesis
.
Gastroenterol Hepatol (N Y)
2
,
282
291
[PubMed]
46.
Li
X.
,
Song
D.
and
Leng
S.X.
(
2015
)
Link between type 2 diabetes and Alzheimer's disease: from epidemiology to mechanism and treatment
.
Clin. Interv. Aging.
10
,
549
560
[PubMed]
47.
Maletinska
L.
,
Popelova
A.
,
Zelezna
B.
,
Bencze
M.
and
Kunes
J.
(
2019
)
The impact of anorexigenic peptides in experimental models of Alzheimer's disease pathology
.
J. Endocrinol.
240
,
R47
R72
[PubMed]
48.
Chen
X.Y.
,
Du
Y.F.
and
Chen
L.
(
2018
)
Neuropeptides exert neuroprotective effects in Alzheimer's disease
.
Front. Mol. Neurosci.
11
,
493
[PubMed]
49.
Holscher
C.
(
2018
)
Novel dual GLP-1/GIP receptor agonists show neuroprotective effects in Alzheimer's and Parkinson's disease models
.
Neuropharmacology
136
,
251
259
[PubMed]
50.
Cummings
J.L.
,
Osse
A.M.L.
and
Kinney
J.W.
(
2023
)
Alzheimer's disease: novel targets and investigational drugs for disease modification
.
Drugs
83
,
1387
1408
[PubMed]
51.
Paladugu
L.
,
Gharaibeh
A.
,
Kolli
N.
,
Learman
C.
,
Hall
T.C.
,
Li
L.
et al.
(
2021
)
Liraglutide has anti-inflammatory and anti-amyloid properties in streptozotocin-induced and 5xFAD mouse models of Alzheimer's Disease
.
Int. J. Mol. Sci.
22
,
52.
Bader
M.
,
Li
Y.
,
Tweedie
D.
,
Shlobin
N.A.
,
Bernstein
A.
,
Rubovitch
V.
et al.
(
2019
)
Neuroprotective effects and treatment potential of incretin mimetics in a murine model of mild traumatic brain injury
.
Front Cell Dev. Biol.
7
,
356
[PubMed]
53.
Batista
A.F.
,
Forny-Germano
L.
,
Clarke
J.R.
,
Lyra
E.S.N.M.
,
Brito-Moreira
J.
,
Boehnke
S.E.
et al.
(
2018
)
The diabetes drug liraglutide reverses cognitive impairment in mice and attenuates insulin receptor and synaptic pathology in a non-human primate model of Alzheimer's disease
.
J. Pathol.
245
,
85
100
[PubMed]
54.
Holubova
M.
,
Hruba
L.
,
Popelova
A.
,
Bencze
M.
,
Prazienkova
V.
,
Gengler
S.
et al.
(
2019
)
Liraglutide and a lipidized analog of prolactin-releasing peptide show neuroprotective effects in a mouse model of beta-amyloid pathology
.
Neuropharmacology
144
,
377
387
[PubMed]
55.
Duarte-Neves
J.
,
Pereira de Almeida
L.
and
Cavadas
C.
(
2016
)
Neuropeptide Y (NPY) as a therapeutic target for neurodegenerative diseases
.
Neurobiol. Dis.
95
,
210
224
[PubMed]
56.
Pain
S.
,
Brot
S.
and
Gaillard
A.
(
2022
)
Neuroprotective effects of neuropeptide Y against neurodegenerative disease
.
Curr. Neuropharmacol.
20
,
1717
1725
[PubMed]
57.
Reichmann
F.
and
Holzer
P.
(
2016
)
Neuropeptide Y: A stressful review
.
Neuropeptides
55
,
99
109
[PubMed]
58.
dos Santos
V.V.
,
Santos
D.B.
,
Lach
G.
,
Rodrigues
A.L.S.
,
Farina
M.
,
De Lima
T.C.M.
et al.
(
2013
)
Neuropeptide Y (NPY) prevents depressive-like behavior, spatial memory deficits and oxidative stress following amyloid-β (Aβ1–40) administration in mice
.
Behav. Brain Res.
244
,
107
115
[PubMed]
59.
Lee
N.K.
,
Park
S.E.
,
Kwon
S.J.
,
Shim
S.
,
Byeon
Y.
,
Kim
J.-H.
et al.
(
2017
)
Agouti related peptide secreted via human mesenchymal stem cells upregulates proteasome activity in an Alzheimer's disease model
.
Sci. Rep.
7
,
39340
[PubMed]
60.
Calafate
S.
,
Ozturan
G.
,
Thrupp
N.
,
Vanderlinden
J.
,
Santa-Marinha
L.
,
Morais-Ribeiro
R.
et al.
(
2023
)
Early alterations in the MCH system link aberrant neuronal activity and sleep disturbances in a mouse model of Alzheimer's disease
.
Nat. Neurosci.
26
,
1021
1031
[PubMed]
61.
Oh
S.T.
,
Liu
Q.F.
,
Jeong
H.J.
,
Lee
S.
,
Samidurai
M.
,
Jo
J.
et al.
(
2019
)
Nasal cavity administration of melanin-concentrating hormone improves memory impairment in memory-impaired and Alzheimer's disease mouse models
.
Mol. Neurobiol.
56
,
8076
8086
[PubMed]
62.
Monzon
M.E.
,
de Souza
M.M.
,
Izquierdo
L.A.
,
Izquierdo
I.
,
Barros
D.M.
and
de Barioglio
S.R.
(
1999
)
Melanin-concentrating hormone (MCH) modifies memory retention in rats ☆
.
Peptides
20
,
1517
1519
[PubMed]
63.
Varas
M.
,
Pérez
M.
,
Monzón
M.E.
and
de Barioglio
S.R.
(
2002
)
Melanin-concentrating hormone, hippocampal nitric oxide levels and memory retention
.
Peptides
23
,
2213
2221
[PubMed]
64.
Varas
M.M.
,
Pérez
M.F.
,
Ramı́rez
O.A.
and
de Barioglio
S.R.
(
2003
)
Increased susceptibility to LTP generation and changes in NMDA-NR1 and -NR2B subunits mRNA expression in rat hippocampus after MCH administration
.
Peptides
24
,
1403
1411
[PubMed]
65.
Couvineau
A.
,
Voisin
T.
,
Nicole
P.
,
Gratio
V.
,
Abad
C.
and
Tan
Y.V.
(
2019
)
Orexins as novel therapeutic targets in inflammatory and neurodegenerative diseases
.
Front Endocrinol. (Lausanne)
10
,
709
[PubMed]
66.
Becquet
L.
,
Abad
C.
,
Leclercq
M.
,
Miel
C.
,
Jean
L.
,
Riou
G.
et al.
(
2019
)
Systemic administration of orexin A ameliorates established experimental autoimmune encephalomyelitis by diminishing neuroinflammation
.
J. Neuroinflamm.
16
,
64
[PubMed]
67.
Liu
M.F.
,
Xue
Y.
,
Liu
C.
,
Liu
Y.H.
,
Diao
H.L.
,
Wang
Y.
et al.
(
2018
)
Orexin-A exerts neuroprotective effects via OX1R in Parkinson's disease
.
Front Neurosci.
12
,
835
[PubMed]
68.
Borroto-Escuela
D.O.
,
Fores
R.
,
Pita
M.
,
Barbancho
M.A.
,
Zamorano-Gonzalez
P.
,
Casares
N.G.
et al.
(
2022
)
Intranasal delivery of galanin 2 and neuropeptide Y1 agonists enhanced spatial memory performance and neuronal precursor cells proliferation in the dorsal hippocampus in rats
.
Front Pharmacol.
13
,
820210
[PubMed]
69.
Beltran-Casanueva
R.
,
Hernández-García
A.
,
de Amo García
P.
,
Blanco-Reina
E.
,
Serrano-Castro
P.
,
García-Casares
N.
et al.
(
2024
)
Neuropeptide Y receptor 1 and galanin receptor 2 (NPY1R-GALR2) interactions in the dentate gyrus and their relevance for neurogenesis and cognition
.
Front Cell Neurosci.
18
,
1323986
[PubMed]
70.
Abbosh
C.
,
Lawkowski
A.
,
Zaben
M.
and
Gray
W.
(
2011
)
GalR2/3 mediates proliferative and trophic effects of galanin on postnatal hippocampal precursors
.
J. Neurochem.
117
,
425
436
[PubMed]
71.
Bertolini
A.
,
Tacchi
R.
and
Vergoni
A.V.
(
2009
)
Brain effects of melanocortins
.
Pharmacol. Res.
59
,
13
47
[PubMed]
72.
Harno
E.
and
White
A.
(
2016
)
Chapter 8 - Adrenocorticotropic Hormone
. In
Endocrinology: Adult and Pediatric (Seventh Edition)
(
Jameson
J.L.
,
De Groot
L.J.
,
de Kretser
D.M.
,
Giudice
L.C.
,
Grossman
A.B.
,
Melmed
S.
et al.
, eds), pp.
129.e5
146.e5
,
W.B. Saunders
,
Philadelphia
73.
Day
R.
(
2009
)
Proopiomelanocortin
.
Encyclopedia Neurosci.
1139
1141
74.
Dores
R.M.
(
2009
)
Adrenocorticotropic hormone, melanocyte-stimulating hormone, and the melanocortin receptors: revisiting the work of Robert Schwyzer: a thirty-year retrospective
.
Ann. N. Y. Acad. Sci.
1163
,
93
100
[PubMed]
75.
Wikberg
J.E.
,
Muceniece
R.
,
Mandrika
I.
,
Prusis
P.
,
Lindblom
J.
,
Post
C.
et al.
(
2000
)
New aspects on the melanocortins and their receptors
.
Pharmacol. Res.
42
,
393
420
[PubMed]
76.
Cone
R.D.
(
2006
)
Studies on the physiological functions of the melanocortin system
.
Endocr. Rev.
27
,
736
749
[PubMed]
77.
Yanik
T.
and
Durhan
S.T.
(
2023
)
Specific functions of melanocortin 3 receptor (MC3R)
.
J. Clin. Res. Pediatr Endocrinol.
15
,
1
6
[PubMed]
78.
Ollmann
M.M.
,
Wilson
B.D.
,
Yang
Y.K.
,
Kerns
J.A.
,
Chen
Y.
,
Gantz
I.
et al.
(
1997
)
Antagonism of central melanocortin receptors in vitro and in vivo by agouti-related protein
.
Science
278
,
135
138
[PubMed]
79.
Dutia
R.
,
Kim
A.J.
,
Modes
M.
,
Rothlein
R.
,
Shen
J.M.
,
Tian
Y.E.
et al.
(
2013
)
Effects of AgRP inhibition on energy balance and metabolism in rodent models
.
PLoS ONE
8
,
e65317
[PubMed]
80.
Smith
A.I.
and
Funder
J.W.
(
1988
)
Proopiomelanocortin processing in the pituitary, central nervous system, and peripheral tissues
.
Endocr. Rev.
9
,
159
179
[PubMed]
81.
Kuhnen
P.
,
Krude
H.
and
Biebermann
H.
(
2019
)
Melanocortin-4 receptor signalling: importance for weight regulation and obesity treatment
.
Trends Mol. Med.
25
,
136
148
[PubMed]
82.
Irani
B.G.
,
Xiang
Z.
,
Yarandi
H.N.
,
Holder
J.R.
,
Moore
M.C.
,
Bauzo
R.M.
et al.
(
2011
)
Implication of the melanocortin-3 receptor in the regulation of food intake
.
Eur. J. Pharmacol.
660
,
80
87
[PubMed]
83.
Huszar
D.
,
Lynch
C.A.
,
Fairchild-Huntress
V.
,
Dunmore
J.H.
,
Fang
Q.
,
Berkemeier
L.R.
et al.
(
1997
)
Targeted disruption of the melanocortin-4 receptor results in obesity in mice
.
Cell
88
,
131
141
[PubMed]
84.
Chen
A.S.
,
Marsh
D.J.
,
Trumbauer
M.E.
,
Frazier
E.G.
,
Guan
X.M.
,
Yu
H.
et al.
(
2000
)
Inactivation of the mouse melanocortin-3 receptor results in increased fat mass and reduced lean body mass
.
Nat. Genet.
26
,
97
102
[PubMed]
85.
Farooqi
I.S.
,
Yeo
G.S.
,
Keogh
J.M.
,
Aminian
S.
,
Jebb
S.A.
,
Butler
G.
et al.
(
2000
)
Dominant and recessive inheritance of morbid obesity associated with melanocortin 4 receptor deficiency
.
J. Clin. Invest.
106
,
271
279
[PubMed]
86.
Krude
H.
,
Biebermann
H.
,
Luck
W.
,
Horn
R.
,
Brabant
G.
and
Gruters
A.
(
1998
)
Severe early-onset obesity, adrenal insufficiency and red hair pigmentation caused by POMC mutations in humans
.
Nat. Genet.
19
,
155
157
[PubMed]
87.
Butler
A.A.
and
Cone
R.D.
(
2002
)
The melanocortin receptors: lessons from knockout models
.
Neuropeptides
36
,
77
84
[PubMed]
88.
Hansen
M.J.
,
Schioth
H.B.
and
Morris
M.J.
(
2005
)
Feeding responses to a melanocortin agonist and antagonist in obesity induced by a palatable high-fat diet
.
Brain Res.
1039
,
137
145
[PubMed]
89.
Clegg
D.J.
,
Benoit
S.C.
,
Air
E.L.
,
Jackman
A.
,
Tso
P.
,
D'Alessio
D.
et al.
(
2003
)
Increased dietary fat attenuates the anorexic effects of intracerebroventricular injections of MTII
.
Endocrinology
144
,
2941
2946
[PubMed]
90.
Fan
W.
,
Boston
B.A.
,
Kesterson
R.A.
,
Hruby
V.J.
and
Cone
R.D.
(
1997
)
Role of melanocortinergic neurons in feeding and the agouti obesity syndrome
.
Nature
385
,
165
168
[PubMed]
91.
Marsh
D.J.
,
Hollopeter
G.
,
Huszar
D.
,
Laufer
R.
,
Yagaloff
K.A.
,
Fisher
S.L.
et al.
(
1999
)
Response of melanocortin-4 receptor-deficient mice to anorectic and orexigenic peptides
.
Nat. Genet.
21
,
119
122
[PubMed]
92.
Chen
A.S.
,
Metzger
J.M.
,
Trumbauer
M.E.
,
Guan
X.M.
,
Yu
H.
,
Frazier
E.G.
et al.
(
2000
)
Role of the melanocortin-4 receptor in metabolic rate and food intake in mice
.
Transgenic Res.
9
,
145
154
[PubMed]
93.
Conde-Frieboes
K.
,
Thogersen
H.
,
Lau
J.F.
,
Sensfuss
U.
,
Hansen
T.K.
,
Christensen
L.
et al.
(
2012
)
Identification and in vivo and in vitro characterization of long acting and melanocortin 4 receptor (MC4-R) selective alpha-melanocyte-stimulating hormone (alpha-MSH) analogues
.
J. Med. Chem.
55
,
1969
1977
[PubMed]
94.
Fosgerau
K.
,
Raun
K.
,
Nilsson
C.
,
Dahl
K.
and
Wulff
B.S.
(
2014
)
Novel alpha-MSH analog causes weight loss in obese rats and minipigs and improves insulin sensitivity
.
J. Endocrinol.
220
,
97
107
[PubMed]
95.
Rodrigues
A.R.
,
Salazar
M.J.
,
Rocha-Rodrigues
S.
,
Goncalves
I.O.
,
Cruz
C.
,
Neves
D.
et al.
(
2019
)
Peripherally administered melanocortins induce mice fat browning and prevent obesity
.
Int. J. Obes. (Lond.)
43
,
1058
1069
[PubMed]
96.
Kumar
K.G.
,
Sutton
G.M.
,
Dong
J.Z.
,
Roubert
P.
,
Plas
P.
,
Halem
H.A.
et al.
(
2009
)
Analysis of the therapeutic functions of novel melanocortin receptor agonists in MC3R- and MC4R-deficient C57BL/6J mice
.
Peptides
30
,
1892
1900
[PubMed]
97.
Ma
K.
and
McLaurin
J.
(
2017
)
alpha-melanocyte stimulating hormone as a potential therapy for Alzheimer’s disease
.
Curr Alzheimer Res.
14
,
18
29
[PubMed]
98.
Costa
A.
,
Bini
P.
,
Hamze-Sinno
M.
,
Moglia
A.
,
Franciotta
D.
,
Sinforiani
E.
et al.
(
2011
)
Galanin and alpha-MSH autoantibodies in cerebrospinal fluid of patients with Alzheimer's disease
.
J. Neuroimmunol.
240-241
,
114
120
[PubMed]
99.
Arai
H.
,
Moroji
T.
,
Kosaka
K.
and
Iizuka
R.
(
1986
)
Extrahypophyseal distribution of alpha-melanocyte stimulating hormone (alpha-MSH)-like immunoreactivity in postmortem brains from normal subjects and Alzheimer-type dementia patients
.
Brain Res.
377
,
305
310
[PubMed]
100.
Ma
K.
and
McLaurin
J.
(
2014
)
alpha-Melanocyte stimulating hormone prevents GABAergic neuronal loss and improves cognitive function in Alzheimer's disease
.
J. Neurosci.
34
,
6736
6745
[PubMed]
101.
Forslin Aronsson
S.
,
Spulber
S.
,
Popescu
L.M.
,
Winblad
B.
,
Post
C.
,
Oprica
M.
et al.
(
2006
)
alpha-Melanocyte-stimulating hormone is neuroprotective in rat global cerebral ischemia
.
Neuropeptides
40
,
65
75
[PubMed]
102.
Giuliani
D.
,
Zaffe
D.
,
Ottani
A.
,
Spaccapelo
L.
,
Galantucci
M.
,
Minutoli
L.
et al.
(
2011
)
Treatment of cerebral ischemia with melanocortins acting at MC4 receptors induces marked neurogenesis and long-lasting functional recovery
.
Acta Neuropathol.
122
,
443
453
[PubMed]
103.
Giuliani
D.
,
Bitto
A.
,
Galantucci
M.
,
Zaffe
D.
,
Ottani
A.
,
Irrera
N.
et al.
(
2014
)
Melanocortins protect against progression of Alzheimer's disease in triple-transgenic mice by targeting multiple pathophysiological pathways
.
Neurobiol. Aging
35
,
537
547
[PubMed]
104.
Daini
E.
,
Vandini
E.
,
Bodria
M.
,
Liao
W.
,
Baraldi
C.
,
Secco
V.
et al.
(
2022
)
Melanocortin receptor agonist NDP-alpha-MSH improves cognitive deficits and microgliosis but not amyloidosis in advanced stages of AD progression in 5XFAD and 3xTg mice
.
Front Immunol.
13
,
1082036
[PubMed]
105.
Giuliani
D.
,
Galantucci
M.
,
Neri
L.
,
Canalini
F.
,
Calevro
A.
,
Bitto
A.
et al.
(
2014
)
Melanocortins protect against brain damage and counteract cognitive decline in a transgenic mouse model of moderate Alzheimer's disease
.
Eur. J. Pharmacol.
740
,
144
150
[PubMed]
106.
Giuliani
D.
,
Neri
L.
,
Canalini
F.
,
Calevro
A.
,
Ottani
A.
,
Vandini
E.
et al.
(
2015
)
NDP-alpha-MSH induces intense neurogenesis and cognitive recovery in Alzheimer transgenic mice through activation of melanocortin MC4 receptors
.
Mol. Cell. Neurosci.
67
,
13
21
[PubMed]
107.
Johnson
G.V.
and
Bailey
C.D.
(
2003
)
The p38 MAP kinase signaling pathway in Alzheimer's disease
.
Exp. Neurol.
183
,
263
268
[PubMed]
108.
Lau
J.K.Y.
,
Tian
M.
,
Shen
Y.
,
Lau
S.F.
,
Fu
W.Y.
,
Fu
A.K.Y.
et al.
(
2021
)
Melanocortin receptor activation alleviates amyloid pathology and glial reactivity in an Alzheimer's disease transgenic mouse model
.
Sci. Rep.
11
,
4359
[PubMed]
109.
Douglass
J.
,
McKinzie
A.A.
and
Couceyro
P.
(
1995
)
PCR differential display identifies a rat brain mRNA that is transcriptionally regulated by cocaine and amphetamine
.
J. Neurosci.
15
,
2471
2481
[PubMed]
110.
Thim
L.
,
Kristensen
P.
,
Nielsen
P.F.
,
Wulff
B.S.
and
Clausen
J.T.
(
1999
)
Tissue-specific processing of cocaine- and amphetamine-regulated transcript peptides in the rat
.
Proc. Natl. Acad Sci. U.S.A.
96
,
2722
2727
[PubMed]
111.
Thim
L.
,
Nielsen
P.F.
,
Judge
M.E.
,
Andersen
A.S.
,
Diers
I.
,
Egel-Mitani
M.
et al.
(
1998
)
Purification and characterisation of a new hypothalamic satiety peptide, cocaine and amphetamine regulated transcript (CART), produced in yeast
.
FEBS Lett.
428
,
263
268
[PubMed]
112.
Dey
A.
,
Xhu
X.
,
Carroll
R.
,
Turck
C.W.
,
Stein
J.
and
Steiner
D.F.
(
2003
)
Biological processing of the cocaine and amphetamine-regulated transcript precursors by prohormone convertases, PC2 and PC1/3
.
J. Biol. Chem.
278
,
15007
15014
[PubMed]
113.
Stein
J.
,
Steiner
D.F.
and
Dey
A.
(
2006
)
Processing of cocaine- and amphetamine-regulated transcript (CART) precursor proteins by prohormone convertases (PCs) and its implications
.
Peptides
27
,
1919
1925
[PubMed]
114.
Spiess
J.
,
Villarreal
J.
and
Vale
W.J.B.
(
1981
)
Isolation and sequence analysis of a somatostatin-like polypeptide from ovine hypothalamus
.
20
,
1982
1988
[PubMed]
115.
Dominguez
G.
(
2006
)
The CART gene: structure and regulation
.
Peptides
27
,
1913
1918
[PubMed]
116.
Douglass
J.
and
Daoud
S.
(
1996
)
Characterization of the human cDNA and genomic DNA encoding CART: a cocaine- and amphetamine-regulated transcript
.
Gene
169
,
241
245
[PubMed]
117.
Yermolaieva
O.
,
Chen
J.
,
Couceyro
P.R.
and
Hoshi
T.
(
2001
)
Cocaine- and amphetamine-regulated transcript peptide modulation of voltage-gated Ca2+ signaling in hippocampal neurons
.
J. Neurosci.
21
,
7474
7480
[PubMed]
118.
Lakatos
A.
,
Prinster
S.
,
Vicentic
A.
,
Hall
R.A.
and
Kuhar
M.J.
(
2005
)
Cocaine- and amphetamine-regulated transcript (CART) peptide activates the extracellular signal-regulated kinase (ERK) pathway in AtT20 cells via putative G-protein coupled receptors
.
Neurosci. Lett.
384
,
198
202
[PubMed]
119.
Vicentic
A.
,
Lakatos
A.
and
Kuhar
M.J.
(
2005
)
CART (cocaine- and amphetamine-regulated transcript) peptide receptors: specific binding in AtT20 cells
.
Eur. J. Pharmacol.
528
,
188
189
[PubMed]
120.
Maletinska
L.
,
Maixnerova
J.
,
Matyskova
R.
,
Haugvicova
R.
,
Sloncova
E.
,
Elbert
T.
et al.
(
2007
)
Cocaine- and amphetamine-regulated transcript (CART) peptide specific binding in pheochromocytoma cells PC12
.
Eur. J. Pharmacol.
559
,
109
114
[PubMed]
121.
Nagelova
V.
,
Pirnik
Z.
,
Zelezna
B.
and
Maletinska
L.
(
2014
)
CART (cocaine- and amphetamine-regulated transcript) peptide specific binding sites in PC12 cells have characteristics of CART peptide receptors
.
Brain Res.
1547
,
16
24
[PubMed]
122.
Yosten
G.L.
,
Harada
C.M.
,
Haddock
C.
,
Giancotti
L.A.
,
Kolar
G.R.
,
Patel
R.
et al.
(
2020
)
GPR160 de-orphanization reveals critical roles in neuropathic pain in rodents
.
J. Clin. Invest.
130
,
2587
2592
[PubMed]
123.
Freitas-Lima
L.C.
,
Pacesova
A.
,
Stanurova
J.
,
Sacha
P.
,
Marek
A.
,
Hubalek
M.
et al.
(
2023
)
GPR160 is not a receptor of anorexigenic cocaine- and amphetamine-regulated transcript peptide
.
Eur. J. Pharmacol.
949
,
175713
[PubMed]
124.
Gautvik
K.M.
,
de Lecea
L.
,
Gautvik
V.T.
,
Danielson
P.E.
,
Tranque
P.
,
Dopazo
A.
et al.
(
1996
)
Overview of the most prevalent hypothalamus-specific mRNAs, as identified by directional tag PCR subtraction
.
Proc. Natl. Acad Sci. U.S.A.
93
,
8733
8738
[PubMed]
125.
Koylu
E.O.
,
Couceyro
P.R.
,
Lambert
P.D.
,
Ling
N.C.
,
DeSouza
E.B.
and
Kuhar
M.J.
(
1997
)
Immunohistochemical localization of novel CART peptides in rat hypothalamus, pituitary and adrenal gland
.
J. Neuroendocrinol.
9
,
823
833
[PubMed]
126.
Jensen
P.B.
,
Kristensen
P.
,
Clausen
J.T.
,
Judge
M.E.
,
Hastrup
S.
,
Thim
L.
et al.
(
1999
)
The hypothalamic satiety peptide CART is expressed in anorectic and non-anorectic pancreatic islet tumors and in the normal islet of Langerhans
.
FEBS Lett.
447
,
139
143
[PubMed]
127.
Ekblad
E.
(
2006
)
CART in the enteric nervous system
.
Peptides
27
,
2024
2030
[PubMed]
128.
Koylu
E.O.
,
Couceyro
P.R.
,
Lambert
P.D.
and
Kuhar
M.J.
(
1998
)
Cocaine- and amphetamine-regulated transcript peptide immunohistochemical localization in the rat brain
.
J. Comp. Neurol.
391
,
115
132
[PubMed]
129.
Asnicar
M.A.
,
Smith
D.P.
,
Yang
D.D.
,
Heiman
M.L.
,
Fox
N.
,
Chen
Y.F.
et al.
(
2001
)
Absence of cocaine- and amphetamine-regulated transcript results in obesity in mice fed a high caloric diet
.
Endocrinology
142
,
4394
4400
[PubMed]
130.
Wierup
N.
,
Richards
W.G.
,
Bannon
A.W.
,
Kuhar
M.J.
,
Ahrén
B.
and
Sundler
F.
(
2005
)
CART knock out mice have impaired insulin secretion and glucose intolerance, altered beta cell morphology and increased body weight
.
Regul. Pept.
129
,
203
211
[PubMed]
131.
Bannon
A.W.
,
Seda
J.
,
Carmouche
M.
,
Francis
J.M.
,
Jarosinski
M.A.
and
Douglass
J.
(
2001
)
Multiple behavioral effects of cocaine- and amphetamine-regulated transcript (CART) peptides in mice: CART 42-89 and CART 49-89 differ in potency and activity
.
J. Pharmacol. Exp. Ther.
299
,
1021
1026
[PubMed]
132.
Lambert
P.D.
,
Couceyro
P.R.
,
McGirr
K.M.
,
Dall Vechia
S.E.
,
Smith
Y.
and
Kuhar
M.J.
(
1998
)
CART peptides in the central control of feeding and interactions with neuropeptide Y
.
Synapse
29
,
293
298
[PubMed]
133.
Kristensen
P.
,
Judge
M.E.
,
Thim
L.
,
Ribel
U.
,
Christjansen
K.N.
,
Wulff
B.S.
et al.
(
1998
)
Hypothalamic CART is a new anorectic peptide regulated by leptin
.
Nature
393
,
72
76
[PubMed]
134.
Wang
Z.W.
,
Zhou
Y.T.
,
Kakuma
T.
,
Lee
Y.
,
Higa
M.
,
Kalra
S.P.
et al.
(
1999
)
Comparing the hypothalamic and extrahypothalamic actions of endogenous hyperleptinemia
.
Proc. Natl. Acad Sci. U.S.A.
96
,
10373
10378
[PubMed]
135.
Elias
C.F.
,
Lee
C.E.
,
Kelly
J.F.
,
Ahima
R.S.
,
Kuhar
M.
,
Saper
C.B.
et al.
(
2001
)
Characterization of CART neurons in the rat and human hypothalamus
.
J. Comp. Neurol.
432
,
1
19
[PubMed]
136.
Tian
D.R.
,
Li
X.D.
,
Shi
Y.S.
,
Wan
Y.
,
Wang
X.M.
,
Chang
J.K.
et al.
(
2004
)
Changes of hypothalamic alpha-MSH and CART peptide expression in diet-induced obese rats
.
Peptides
25
,
2147
2153
[PubMed]
137.
Fekete
C.
,
Mihaly
E.
,
Luo
L.G.
,
Kelly
J.
,
Clausen
J.T.
,
Mao
Q.
et al.
(
2000
)
Association of cocaine- and amphetamine-regulated transcript-immunoreactive elements with thyrotropin-releasing hormone-synthesizing neurons in the hypothalamic paraventricular nucleus and its role in the regulation of the hypothalamic-pituitary-thyroid axis during fasting
.
J. Neurosci.
20
,
9224
9234
[PubMed]
138.
Fekete
C.
and
Lechan
R.M.
(
2006
)
Neuroendocrine implications for the association between cocaine- and amphetamine regulated transcript (CART) and hypophysiotropic thyrotropin-releasing hormone (TRH)
.
Peptides
27
,
2012
2018
[PubMed]
139.
Pirnik
Z.
,
Maixnerova
J.
,
Matyskova
R.
,
Koutova
D.
,
Zelezna
B.
,
Maletinska
L.
et al.
(
2010
)
Effect of anorexinergic peptides, cholecystokinin (CCK) and cocaine and amphetamine regulated transcript (CART) peptide, on the activity of neurons in hypothalamic structures of C57Bl/6 mice involved in the food intake regulation
.
Peptides
31
,
139
144
[PubMed]
140.
Maletinska
L.
,
Maixnerova
J.
,
Matyskova
R.
,
Haugvicova
R.
,
Pirnik
Z.
,
Kiss
A.
et al.
(
2008
)
Synergistic effect of CART (cocaine- and amphetamine-regulated transcript) peptide and cholecystokinin on food intake regulation in lean mice
.
BMC Neuroscience
9
,
101
[PubMed]
141.
Rohner-Jeanrenaud
F.
,
Craft
L.S.
,
Bridwell
J.
,
Suter
T.M.
,
Tinsley
F.C.
,
Smiley
D.L.
et al.
(
2002
)
Chronic central infusion of cocaine- and amphetamine-regulated transcript (CART 55-102): effects on body weight homeostasis in lean and high-fat-fed obese rats
.
Int. J. Obes. Relat. Metab. Disord.
26
,
143
149
[PubMed]
142.
Wortley
K.E.
,
Chang
G.Q.
,
Davydova
Z.
,
Fried
S.K.
and
Leibowitz
S.F.
(
2004
)
Cocaine- and amphetamine-regulated transcript in the arcuate nucleus stimulates lipid metabolism to control body fat accrual on a high-fat diet
.
Regul. Pept.
117
,
89
99
[PubMed]
143.
Upadhya
M.A.
,
Nakhate
K.T.
,
Kokare
D.M.
,
Singru
P.S.
and
Subhedar
N.K.
(
2011
)
Cocaine- and amphetamine-regulated transcript peptide increases spatial learning and memory in rats
.
Life Sci.
88
,
322
334
[PubMed]
144.
Jin
J.L.
,
Liou
A.K.
,
Shi
Y.
,
Yin
K.L.
,
Chen
L.
,
Li
L.L.
et al.
(
2015
)
CART treatment improves memory and synaptic structure in APP/PS1 mice
.
Sci. Rep.
5
,
10224
[PubMed]
145.
Yin
K.
,
Jin
J.
,
Zhu
X.
,
Yu
L.
,
Wang
S.
,
Qian
L.
et al.
(
2017
)
CART modulates beta-amyloid metabolism-associated enzymes and attenuates memory deficits in APP/PS1 mice
.
Neurol. Res.
39
,
885
894
[PubMed]
146.
Jiang
H.
,
Niu
F.
,
Zheng
Y.
and
Xu
Y.
(
2021
)
CART mitigates oxidative stress and DNA damage in memory deficits of APP/PS1 mice via upregulating beta-amyloid metabolism-associated enzymes
.
Mol. Med. Rep.
23
,
147.
Jiao
W.
,
Wang
Y.
,
Kong
L.
,
Ou-Yang
T.
,
Meng
Q.
,
Fu
Q.
et al.
(
2018
)
CART peptide activates the Nrf2/HO-1 antioxidant pathway and protects hippocampal neurons in a rat model of Alzheimer's disease
.
Biochem. Biophys. Res. Commun.
501
,
1016
1022
[PubMed]
148.
Hannibal
J.
,
Mikkelsen
J.D.
,
Clausen
H.
,
Holst
J.J.
,
Wulff
B.S.
and
Fahrenkrug
J.
(
1995
)
Gene expression of pituitary adenylate cyclase activating polypeptide (PACAP) in the rat hypothalamus
.
Regul. Pept.
55
,
133
148
[PubMed]
149.
Kivipelto
L.
,
Absood
A.
,
Arimura
A.
,
Sundler
F.
,
Hakanson
R.
and
Panula
P.
(
1992
)
The distribution of pituitary adenylate cyclase-activating polypeptide-like immunoreactivity is distinct from helodermin- and helospectin-like immunoreactivities in the rat brain
.
J. Chem. Neuroanat.
5
,
85
94
[PubMed]
150.
Koves
K.
,
Arimura
A.
,
Gorcs
T.G.
and
Somogyvari-Vigh
A.
(
1991
)
Comparative distribution of immunoreactive pituitary adenylate cyclase activating polypeptide and vasoactive intestinal polypeptide in rat forebrain
.
Neuroendocrinology
54
,
159
169
[PubMed]
151.
Sureshkumar
K.
,
Saenz
A.
,
Ahmad
S.M.
and
Lutfy
K.
(
2021
)
The PACAP/PAC1 receptor system and feeding
.
Brain Sci.
12
,
[PubMed]
152.
Hawke
Z.
,
Ivanov
T.R.
,
Bechtold
D.A.
,
Dhillon
H.
,
Lowell
B.B.
and
Luckman
S.M.
(
2009
)
PACAP neurons in the hypothalamic ventromedial nucleus are targets of central leptin signaling
.
J. Neurosci.
29
,
14828
14835
[PubMed]
153.
Mata-Pacheco
V.
,
Hernandez
J.
,
Varma
N.
,
Xu
J.
,
Sayers
S.
,
Le
N.
et al.
(
2024
)
Dynamic, sex- and diet-specific pleiotropism in the PAC1 receptor-mediated regulation of arcuate proopiomelanocortin and Neuropeptide Y/Agouti related peptide neuronal excitability by anorexigenic ventromedial nucleus PACAP neurons
.
J. Neuroendocrinol.
36
,
e13357
[PubMed]
154.
Adams
B.A.
,
Gray
S.L.
,
Isaac
E.R.
,
Bianco
A.C.
,
Vidal-Puig
A.J.
and
Sherwood
N.M.
(
2008
)
Feeding and metabolism in mice lacking pituitary adenylate cyclase-activating polypeptide
.
Endocrinology
149
,
1571
1580
[PubMed]
155.
Vu
J.P.
,
Luong
L.
,
Sanford
D.
,
Oh
S.
,
Kuc
A.
,
Pisegna
R.
et al.
(
2023
)
PACAP and VIP neuropeptides' and receptors' effects on appetite, satiety and metabolism
.
Biology (Basel.)
12
,
156.
Kondo
T.
,
Tominaga
T.
,
Ichikawa
M.
and
Iijima
T.
(
1997
)
Differential alteration of hippocampal synaptic strength induced by pituitary adenylate cyclase activating polypeptide-38 (PACAP-38)
.
Neurosci. Lett.
221
,
189
192
[PubMed]
157.
Toth
D.
,
Reglodi
D.
,
Schwieters
L.
and
Tamas
A.
(
2023
)
Role of endocrine PACAP in age-related diseases
.
Front Endocrinol. (Lausanne)
14
,
1118927
[PubMed]
158.
Rat
D.
,
Schmitt
U.
,
Tippmann
F.
,
Dewachter
I.
,
Theunis
C.
,
Wieczerzak
E.
et al.
(
2011
)
Neuropeptide pituitary adenylate cyclase-activating polypeptide (PACAP) slows down Alzheimer's disease-like pathology in amyloid precursor protein-transgenic mice
.
FASEB J.
25
,
3208
3218
[PubMed]
159.
Hinuma
S.
,
Habata
Y.
,
Fujii
R.
,
Kawamata
Y.
,
Hosoya
M.
,
Fukusumi
S.
et al.
(
1998
)
A prolactin-releasing peptide in the brain
.
Nature
393
,
272
276
[PubMed]
160.
Samson
W.K.
,
Resch
Z.T.
,
Murphy
T.C.
and
Chang
J.K.
(
1998
)
Gender-biased activity of the novel prolactin releasing peptides: comparison with thyrotropin releasing hormone reveals only pharmacologic effects
.
Endocrine
9
,
289
291
[PubMed]
161.
Jarry
H.
,
Heuer
H.
,
Schomburg
L.
and
Bauer
K.
(
2000
)
Prolactin-releasing peptides do not stimulate prolactin release in vivo
.
Neuroendocrinology
71
,
262
267
,
54544
[PubMed]
162.
Boyle
R.G.
,
Downham
R.
,
Ganguly
T.
,
Humphries
J.
,
Smith
J.
and
Travers
S.
(
2005
)
Structure-activity studies on prolactin-releasing peptide (PrRP). Analogues of PrRP-(19-31)-peptide
.
J. Peptide Sci.
11
,
161
165
[PubMed]
163.
Roland
B.L.
,
Sutton
S.W.
,
Wilson
S.J.
,
Luo
L.
,
Pyati
J.
,
Huvar
R.
et al.
(
1999
)
Anatomical distribution of prolactin-releasing peptide and its receptor suggests additional functions in the central nervous system and periphery
.
Endocrinology
140
,
5736
5745
[PubMed]
164.
Maletinska
L.
,
Spolcova
A.
,
Maixnerova
J.
,
Blechova
M.
and
Zelezna
B.
(
2011
)
Biological properties of prolactin-releasing peptide analogs with a modified aromatic ring of a C-terminal phenylalanine amide
.
Peptides
32
,
1887
1892
[PubMed]
165.
Engstrom
M.
,
Brandt
A.
,
Wurster
S.
,
Savola
J.M.
and
Panula
P.
(
2003
)
Prolactin releasing peptide has high affinity and efficacy at neuropeptide FF2 receptors
.
J. Pharmacol. Exp. Ther.
305
,
825
832
[PubMed]
166.
Maruyama
M.
,
Matsumoto
H.
,
Fujiwara
K.
,
Kitada
C.
,
Hinuma
S.
,
Onda
H.
et al.
(
1999
)
Immunocytochemical localization of prolactin-releasing peptide in the rat brain
.
Endocrinology
140
,
2326
2333
[PubMed]
167.
Matsumoto
H.
,
Murakami
Y.
,
Horikoshi
Y.
,
Noguchi
J.
,
Habata
Y.
,
Kitada
C.
et al.
(
1999
)
Distribution and characterization of immunoreactive prolactin-releasing peptide (PrRP) in rat tissue and plasma
.
Biochem. Biophys. Res. Commun.
257
,
264
268
[PubMed]
168.
Fujii
R.
,
Fukusumi
S.
,
Hosoya
M.
,
Kawamata
Y.
,
Habata
Y.
,
Hinuma
S.
et al.
(
1999
)
Tissue distribution of prolactin-releasing peptide (PrRP) and its receptor
.
Regul. Pept.
83
,
1
10
[PubMed]
169.
Prazienkova
V.
,
Popelova
A.
,
Kunes
J.
and
Maletinska
L.
(
2019
)
Prolactin-releasing peptide: physiological and pharmacological properties
.
Int. J. Mol. Sci.
20
,
[PubMed]
170.
Seal
L.J.
,
Small
C.J.
,
Dhillo
W.S.
,
Stanley
S.A.
,
Abbott
C.R.
,
Ghatei
M.A.
et al.
(
2001
)
PRL-releasing peptide inhibits food intake in male rats via the dorsomedial hypothalamic nucleus and not the paraventricular hypothalamic nucleus
.
Endocrinology
142
,
4236
4243
[PubMed]
171.
Ellacott
K.L.
,
Lawrence
C.B.
,
Pritchard
L.E.
and
Luckman
S.M.
(
2003
)
Repeated administration of the anorectic factor prolactin-releasing peptide leads to tolerance to its effects on energy homeostasis
.
Am. J. Physiol. Regul. Integr. Comp. Physiol.
285
,
R1005
R1010
[PubMed]
172.
Ellacott
K.L.
,
Lawrence
C.B.
,
Rothwell
N.J.
and
Luckman
S.M.
(
2002
)
PRL-releasing peptide interacts with leptin to reduce food intake and body weight
.
Endocrinology
143
,
368
374
[PubMed]
173.
Bechtold
D.A.
and
Luckman
S.M.
(
2006
)
Prolactin-releasing peptide mediates cholecystokinin-induced satiety in mice
.
Endocrinology
147
,
4723
4729
[PubMed]
174.
Takayanagi
Y.
,
Matsumoto
H.
,
Nakata
M.
,
Mera
T.
,
Fukusumi
S.
,
Hinuma
S.
et al.
(
2008
)
Endogenous prolactin-releasing peptide regulates food intake in rodents
.
J. Clin. Invest.
118
,
4014
4024
[PubMed]
175.
Bjursell
M.
,
Lenneras
M.
,
Goransson
M.
,
Elmgren
A.
and
Bohlooly
Y.M.
(
2007
)
GPR10 deficiency in mice results in altered energy expenditure and obesity
.
Biochem. Biophys. Res. Commun.
363
,
633
638
[PubMed]
176.
Prazienkova
V.
,
Funda
J.
,
Pirnik
Z.
,
Karnosova
A.
,
Hruba
L.
,
Korinkova
L.
et al.
(
2021
)
GPR10 gene deletion in mice increases basal neuronal activity, disturbs insulin sensitivity and alters lipid homeostasis
.
Gene
774
,
145427
[PubMed]
177.
Maletinska
L.
,
Nagelova
V.
,
Ticha
A.
,
Zemenova
J.
,
Pirnik
Z.
,
Holubova
M.
et al.
(
2015
)
Novel lipidized analogs of prolactin-releasing peptide have prolonged half-lives and exert anti-obesity effects after peripheral administration
.
Int. J. Obes.
178.
Mikulaskova
B.
,
Zemenova
J.
,
Pirnik
Z.
,
Prazienkova
V.
,
Bednarova
L.
,
Zelezna
B.
et al.
(
2016
)
Effect of palmitoylated prolactin-releasing peptide on food intake and neural activation after different routes of peripheral administration in rats
.
Peptides
75
,
109
117
[PubMed]
179.
Pražienková
V.
,
Holubová
M.
,
Pelantová
H.
,
Bugáňová
M.
,
Pirník
Z.
,
Mikulášková
B.
et al.
(
2017
)
Impact of novel palmitoylated prolactin-releasing peptide analogs on metabolic changes in mice with diet-induced obesity
.
PLoS ONE
12
,
e0183449
[PubMed]
180.
Holubova
M.
,
Hruba
L.
,
Neprasova
B.
,
Majercikova
Z.
,
Lacinova
Z.
,
Kunes
J.
et al.
(
2018
)
Prolactin-releasing peptide improved leptin hypothalamic signaling in obese mice
.
J. Mol. Endocrinol.
60
,
85
94
[PubMed]
181.
Cermakova
M.
,
Pelantova
H.
,
Neprasova
B.
,
Sediva
B.
,
Maletinska
L.
,
Kunes
J.
et al.
(
2019
)
Metabolomic study of obesity and its treatment with palmitoylated prolactin-releasing peptide analog in spontaneously hypertensive and normotensive rats
.
J. Proteome Res.
18
,
1735
1750
[PubMed]
182.
Holubova
M.
,
Zemenova
J.
,
Mikulaskova
B.
,
Panajotova
V.
,
Stohr
J.
,
Haluzik
M.
et al.
(
2016
)
Palmitoylated PrRP analog decreases body weight in DIO rats but not in ZDF rats
.
J. Endocrinol.
229
,
85
96
[PubMed]
183.
Mrazikova
L.
,
Hojna
S.
,
Vaculova
P.
,
Strnad
S.
,
Vrkoslav
V.
,
Pelantova
H.
et al.
(
2023
)
Lipidized PrRP analog exhibits strong anti-obesity and antidiabetic properties in Old WKY rats with obesity and glucose intolerance
.
Nutrients
15
,
[PubMed]
184.
Mrazikova
L.
,
Neprasova
B.
,
Mengr
A.
,
Popelova
A.
,
Strnadova
V.
,
Hola
L.
et al.
(
2021
)
Lipidized prolactin-releasing peptide as a new potential tool to treat obesity and type 2 diabetes mellitus: preclinical studies in rodent models
.
Front Pharmacol.
12
,
779962
[PubMed]
185.
Pflimlin
E.
,
Lear
S.
,
Lee
C.
,
Yu
S.
,
Zou
H.
,
To
A.
et al.
(
2019
)
Design of a long-acting and selective MEG-fatty acid stapled prolactin-releasing peptide analog
.
ACS Med. Chem. Lett.
10
,
1166
1172
[PubMed]
186.
Prazienkova
V.
,
Ticha
A.
,
Blechova
M.
,
Spolcova
A.
,
Zelezna
B.
and
Maletinska
L.
(
2016
)
Pharmacological characterization of lipidized analogs of prolactin-releasing peptide with a modified C- terminal aromatic ring
.
J. Physiol. Pharmacol.
67
,
121
128
[PubMed]
187.
Alexopoulou
F.
,
Bech
E.M.
,
Pedersen
S.L.
,
Thorbek
D.D.
,
Leurs
U.
,
Rudkjaer
L.C.B.
et al.
(
2022
)
Lipidated PrRP31 metabolites are long acting dual GPR10 and NPFF2 receptor agonists with potent body weight lowering effect
.
Sci. Rep.
12
,
1696
[PubMed]
188.
Spolcova
A.
,
Mikulaskova
B.
,
Holubova
M.
,
Nagelova
V.
,
Pirnik
Z.
,
Zemenova
J.
et al.
(
2015
)
Anorexigenic lipopeptides ameliorate central insulin signaling and attenuate tau phosphorylation in hippocampi of mice with monosodium glutamate-induced obesity
.
J. Alzheimers Dis.
45
,
823
835
[PubMed]
189.
Popelova
A.
,
Prazienkova
V.
,
Neprasova
B.
,
Kasperova
B.J.
,
Hruba
L.
,
Holubova
M.
et al.
(
2018
)
Novel lipidized analog of prolactin-releasing peptide improves memory impairment and attenuates hyperphosphorylation of tau protein in a mouse model of tauopathy
.
J. Alzheimers Dis.
62
,
1725
1736
[PubMed]
190.
Mengr
A.
,
Hruba
L.
,
Exnerova
A.
,
Holubova
M.
,
Popelova
A.
,
Zelezna
B.
et al.
(
2021
)
Palmitoylated prolactin-releasing peptide reduced Abeta plaques and microgliosis in the cerebellum: APP/PS1 mice study
.
Curr Alzheimer Res.
[PubMed]
191.
Strnad
S.
,
PraZienkova
V.
,
Holubova
M.
,
Sykora
D.
,
Cvacka
J.
,
Maletinska
L.
et al.
(
2020
)
Mass spectrometry imaging of free-floating brain sections detects pathological lipid distribution in a mouse model of Alzheimer's-like pathology
.
Analyst
[PubMed]
192.
Jorgensen
S.K.
,
Karnosova
A.
,
Mazzaferro
S.
,
Rowley
O.
,
Chen
H.C.
,
Robbins
S.J.
et al.
(
2023
)
An analogue of the prolactin releasing peptide reduces obesity and promotes adult neurogenesis
.
EMBO Rep.
[PubMed]
193.
Macias
M.
,
Acha
B.
,
Corroza
J.
,
Urdanoz-Casado
A.
,
Roldan
M.
,
Robles
M.
et al.
(
2023
)
Liquid biopsy in Alzheimer's disease patients reveals epigenetic changes in the PRLHR gene
.
Cells
12
,
194.
Yang
H.Y.
,
Fratta
W.
,
Majane
E.A.
and
Costa
E.
(
1985
)
Isolation, sequencing, synthesis, and pharmacological characterization of two brain neuropeptides that modulate the action of morphine
.
Proc. Natl. Acad Sci. U.S.A.
82
,
7757
7761
[PubMed]
195.
Panula
P.
,
Aarnisalo
A.A.
and
Wasowicz
K.
(
1996
)
Neuropeptide FF, a mammalian neuropeptide with multiple functions
.
Prog. Neurobiol.
48
,
461
487
[PubMed]
196.
Vilim
F.S.
,
Aarnisalo
A.A.
,
Nieminen
M.L.
,
Lintunen
M.
,
Karlstedt
K.
,
Kontinen
V.K.
et al.
(
1999
)
Gene for pain modulatory neuropeptide NPFF: induction in spinal cord by noxious stimuli
.
Mol. Pharmacol.
55
,
804
811
[PubMed]
197.
Kivipelto
L.
and
Panula
P.
(
1991
)
Central neuronal pathways containing FLFQPQRFamide-like (morphine-modulating) peptides in the rat brain
.
Neuroscience
41
,
137
148
[PubMed]
198.
Jhamandas
J.H.
,
Jhamandas
A.
and
Harris
K.H.
(
2001
)
New central projections of neuropeptide FF: colateral branching pathways in the brainstem and hypothalamus in the rat
.
J. Chem. Neuroanat.
21
,
171
179
[PubMed]
199.
Gouarderes
C.
,
Puget
A.
and
Zajac
J.M.
(
2004
)
Detailed distribution of neuropeptide FF receptors (NPFF1 and NPFF2) in the rat, mouse, octodon, rabbit, guinea pig, and marmoset monkey brains: a comparative autoradiographic study
.
Synapse
51
,
249
269
[PubMed]
200.
Bonini
J.A.
,
Jones
K.A.
,
Adham
N.
,
Forray
C.
,
Artymyshyn
R.
,
Durkin
M.M.
et al.
(
2000
)
Identification and characterization of two G protein-coupled receptors for neuropeptide FF
.
J. Biol. Chem.
275
,
39324
39331
[PubMed]
201.
Roumy
M.
and
Zajac
J.M.
(
1998
)
Neuropeptide FF, pain and analgesia
.
Eur. J. Pharmacol.
345
,
1
11
[PubMed]
202.
Elhabazi
K.
,
Trigo
J.M.
,
Mollereau
C.
,
Mouledous
L.
,
Zajac
J.M.
,
Bihel
F.
et al.
(
2012
)
Involvement of neuropeptide FF receptors in neuroadaptive responses to acute and chronic opiate treatments
.
Br. J. Pharmacol.
165
,
424
435
[PubMed]
203.
Devillers
J.P.
,
Mazarguil
H.
,
Allard
M.
,
Dickenson
A.H.
,
Zajac
J.M.
and
Simonnet
G.
(
1994
)
Characterization of a potent agonist for NPFF receptors: binding study on rat spinal cord membranes
.
Neuropharmacology
33
,
661
669
[PubMed]
204.
Gicquel
S.
,
Mazarguil
H.
,
Allard
M.
,
Simonnet
G.
and
Zajac
J.M.
(
1992
)
Analogues of F8Famide resistant to degradation, with high affinity and in vivo effects
.
Eur. J. Pharmacol.
222
,
61
67
[PubMed]
205.
Vyas
N.
,
Mollereau
C.
,
Cheve
G.
and
McCurdy
C.R.
(
2006
)
Structure-activity relationships of neuropeptide FF and related peptidic and non-peptidic derivatives
.
Peptides
27
,
990
996
[PubMed]
206.
Simonin
F.
,
Schmitt
M.
,
Laulin
J.P.
,
Laboureyras
E.
,
Jhamandas
J.H.
,
MacTavish
D.
et al.
(
2006
)
RF9, a potent and selective neuropeptide FF receptor antagonist, prevents opioid-induced tolerance associated with hyperalgesia
.
Proc. Natl. Acad Sci. U.S.A.
103
,
466
471
[PubMed]
207.
Fang
Q.
,
Wang
Y.Q.
,
He
F.
,
Guo
J.
,
Guo
J.
,
Chen
Q.
et al.
(
2008
)
Inhibition of neuropeptide FF (NPFF)-induced hypothermia and anti-morphine analgesia by RF9, a new selective NPFF receptors antagonist
.
Regul. Pept.
147
,
45
51
[PubMed]
208.
Maletinska
L.
,
Ticha
A.
,
Nagelova
V.
,
Spolcova
A.
,
Blechova
M.
,
Elbert
T.
et al.
(
2013
)
Neuropeptide FF analog RF9 is not an antagonist of NPFF receptor and decreases food intake in mice after its central and peripheral administration
.
Brain Res.
1498
,
33
40
[PubMed]
209.
Murase
T.
,
Arima
H.
,
Kondo
K.
and
Oiso
Y.
(
1996
)
Neuropeptide FF reduces food intake in rats
.
Peptides
17
,
353
354
[PubMed]
210.
Sunter
D.
,
Hewson
A.K.
,
Lynam
S.
and
Dickson
S.L.
(
2001
)
Intracerebroventricular injection of neuropeptide FF, an opioid modulating neuropeptide, acutely reduces food intake and stimulates water intake in the rat
.
Neurosci. Lett.
313
,
145
148
[PubMed]
211.
Nicklous
D.M.
and
Simansky
K.J.
(
2003
)
Neuropeptide FF exerts pro- and anti-opioid actions in the parabrachial nucleus to modulate food intake
.
Am. J. Physiol. Regul. Integr. Comp. Physiol.
285
,
R1046
R1054
[PubMed]
212.
Bechtold
D.A.
and
Luckman
S.M.
(
2007
)
The role of RFamide peptides in feeding
.
J. Endocrinol.
192
,
3
15
[PubMed]
213.
Cline
M.A.
,
Nandar
W.
and
Rogers
J.O.
(
2007
)
Central neuropeptide FF reduces feed consumption and affects hypothalamic chemistry in chicks
.
Neuropeptides
41
,
433
439
[PubMed]
214.
Cline
M.A.
,
Newmyer
B.A.
and
Smith
M.L.
(
2009
)
The anorectic effect of neuropeptide AF is associated with satiety-related hypothalamic nuclei
.
J. Neuroendocrinol.
21
,
595
601
[PubMed]
215.
Maletinska
L.
,
Ticha
A.
,
Nagelova
V.
,
Spolcova
A.
,
Blechova
M.
,
Elbert
T.
et al.
(
2013
)
Neuropeptide FF analog RF9 is not an antagonist of NPFF receptor and decreases food intake in mice after its central and peripheral administration
.
Brain Res.
1498
,
33
40
[PubMed]
216.
Waqas
S.F.H.
,
Hoang
A.C.
,
Lin
Y.T.
,
Ampem
G.
,
Azegrouz
H.
,
Balogh
L.
et al.
(
2017
)
Neuropeptide FF increases M2 activation and self-renewal of adipose tissue macrophages
.
J. Clin. Invest.
127
,
3559
[PubMed]
217.
Strnadova
V.
,
Morgan
A.
,
Skrlova
M.
,
Haasova
E.
,
Bardova
K.
,
Myskova
A.
et al.
(
2024
)
Peripheral administration of lipidized NPAF and NPFF analogs does not influence central food intake regulation but induces anxiety-like behavior
.
Neuropeptides
104
,
102417
[PubMed]
218.
Roth
B.L.
,
Disimone
J.
,
Majane
E.A.
and
Yang
H.Y.
(
1987
)
Elevation of arterial pressure in rats by two new vertebrate peptides FLFQPQRF-NH2 and AGEGLSSPFWSLAAPQRF-NH2 which are immunoreactive to FMRF-NH2 antiserum
.
Neuropeptides
10
,
37
42
[PubMed]
219.
Jhamandas
J.H.
and
Goncharuk
V.
(
2013
)
Role of neuropeptide FF in central cardiovascular and neuroendocrine regulation
.
Front. Endocrinol.
4
,
8
[PubMed]
220.
Desprat
C.
and
Zajac
J.M.
(
1997
)
Hypothermic effects of neuropeptide FF analogues in mice
.
Pharmacol. Biochem. Behav.
58
,
559
563
[PubMed]
221.
Findeisen
M.
,
Rathmann
D.
and
Beck-Sickinger
A.G.
(
2011
)
RFamide peptides: structure, function, mechanisms and pharmaceutical potential
.
4
,
1248
1280
[PubMed]
222.
Kotlinska
J.
,
Pachuta
A.
,
Dylag
T.
and
Silberring
J.
(
2007
)
The role of neuropeptide FF (NPFF) in the expression of sensitization to hyperlocomotor effect of morphine and ethanol
.
Neuropeptides
41
,
51
58
[PubMed]
223.
Kotlinska
J.
,
Pachuta
A.
and
Silberring
J.
(
2008
)
Neuropeptide FF (NPFF) reduces the expression of cocaine-induced conditioned place preference and cocaine-induced sensitization in animals
.
Peptides
29
,
933
939
[PubMed]
224.
Kotlinska
J.H.
,
Gibula-Bruzda
E.
,
Koltunowska
D.
,
Raoof
H.
,
Suder
P.
and
Silberring
J.
(
2012
)
Modulation of neuropeptide FF (NPFF) receptors influences the expression of amphetamine-induced conditioned place preference and amphetamine withdrawal anxiety-like behavior in rats
.
Peptides
33
,
156
163
[PubMed]
225.
Cador
M.
,
Marco
N.
,
Stinus
L.
and
Simonnet
G.
(
2002
)
Interaction between neuropeptide FF and opioids in the ventral tegmental area in the behavioral response to novelty
.
Neuroscience
110
,
309
318
[PubMed]
226.
Kavaliers
M.
and
Colwell
D.D.
(
1993
)
Neuropeptide FF (FLQPQRFamide) and IgG from neuropeptide FF antiserum affect spatial learning in mice
.
Neurosci. Lett.
157
,
75
78
[PubMed]
227.
Betourne
A.
,
Marty
V.
,
Ceccom
J.
,
Halley
H.
,
Lassalle
J.M.
,
Zajac
J.M.
et al.
(
2010
)
Central locomotor and cognitive effects of a NPFF receptor agonist in mouse
.
Peptides
31
,
221
226
[PubMed]
228.
Palotai
M.
,
Telegdy
G.
,
Tanaka
M.
,
Bagosi
Z.
and
Jaszberenyi
M.
(
2014
)
Neuropeptide AF induces anxiety-like and antidepressant-like behavior in mice
.
Behav. Brain Res.
274
,
264
269
[PubMed]
229.
Sun
S.
,
Sun
S.
,
Meng
Y.
,
Shi
B.
and
Chen
Y.
(
2021
)
Elevated serum neuropeptide FF levels are associated with cognitive decline in patients with spinal cord injury
.
Dis. Markers
2021
,
4549049
[PubMed]
230.
Craig
A.
,
Guest
R.
,
Tran
Y.
and
Middleton
J.
(
2017
)
Cognitive impairment and mood states after spinal cord injury
.
J. Neurotrauma
34
,
1156
1163
[PubMed]
231.
Sundblom
D.M.
,
Panula
P.
and
Fyhrquist
F.
(
1995
)
Neuropeptide FF-like immunoreactivity in human plasma
.
Peptides
16
,
347
350
[PubMed]
232.
Guillemin
R.
and
Rosenberg
B.
(
1955
)
Humoral hypothalamic control of anterior pituitary: a study with combined tissue cultures
.
Endocrinology
57
,
599
607
[PubMed]
233.
Vale
W.
,
Spiess
J.
,
Rivier
C.
and
Rivier
J.
(
1981
)
Characterization of a 41-residue ovine hypothalamic peptide that stimulates secretion of corticotropin and beta-endorphin
.
Science
213
,
1394
1397
[PubMed]
234.
Owens
M.J.
and
Nemeroff
C.B.
(
1991
)
Physiology and pharmacology of corticotropin-releasing factor
.
Pharmacol. Rev.
43
,
425
473
[PubMed]
235.
Olschowka
J.A.
,
O'Donohue
T.L.
,
Mueller
G.P.
and
Jacobowitz
D.M.
(
1982
)
The distribution of corticotropin releasing factor-like immunoreactive neurons in rat brain
.
Peptides
3
,
995
1015
[PubMed]
236.
Grammatopoulos
D.K.
and
Ourailidou
S.
(
2017
)
CRH receptor signalling: potential roles in pathophysiology
.
Curr Mol. Pharmacol.
10
,
296
310
[PubMed]
237.
Arase
K.
,
York
D.A.
,
Shimizu
H.
,
Shargill
N.
and
Bray
G.A.
(
1988
)
Effects of corticotropin-releasing factor on food intake and brown adipose tissue thermogenesis in rats
.
Am. J. Physiol.
255
,
E255
E259
[PubMed]
238.
Glowa
J.R.
and
Gold
P.W.
(
1991
)
Corticotropin releasing hormone produces profound anorexigenic effects in the rhesus monkey
.
Neuropeptides
18
,
55
61
[PubMed]
239.
Canet
G.
,
Hernandez
C.
,
Zussy
C.
,
Chevallier
N.
,
Desrumaux
C.
and
Givalois
L.
(
2019
)
Is AD a stress-related disorder? Focus on the HPA axis and its promising therapeutic targets
Front Aging Neurosci.
11
,
269
[PubMed]
240.
Vandael
D.
,
Wierda
K.
,
Vints
K.
,
Baatsen
P.
,
De Groef
L.
,
Moons
L.
et al.
(
2021
)
Corticotropin-releasing factor induces functional and structural synaptic remodelling in acute stress
.
Transl. Psychiatry
11
,
378
[PubMed]
241.
Whitehouse
P.J.
,
Vale
W.W.
,
Zweig
R.M.
,
Singer
H.S.
,
Mayeux
R.
,
Kuhar
M.J.
et al.
(
1987
)
Reductions in corticotropin releasing factor-like immunoreactivity in cerebral cortex in Alzheimer's disease, Parkinson's disease, and progressive supranuclear palsy
.
Neurology
37
,
905
909
[PubMed]
242.
De Souza
E.B.
(
1995
)
Corticotropin-releasing factor receptors: physiology, pharmacology, biochemistry and role in central nervous system and immune disorders
.
Psychoneuroendocrinology
20
,
789
819
[PubMed]
243.
De Souza
E.B.
,
Whitehouse
P.J.
,
Kuhar
M.J.
,
Price
D.L.
and
Vale
W.W.
(
1986
)
Reciprocal changes in corticotropin-releasing factor (CRF)-like immunoreactivity and CRF receptors in cerebral cortex of Alzheimer's disease
.
Nature
319
,
593
595
[PubMed]
244.
Zhang
C.
,
Kuo
C.C.
,
Moghadam
S.H.
,
Monte
L.
,
Campbell
S.N.
,
Rice
K.C.
et al.
(
2016
)
Corticotropin-releasing factor receptor-1 antagonism mitigates beta amyloid pathology and cognitive and synaptic deficits in a mouse model of Alzheimer's disease
.
Alzheimers Dementia
12
,
527
537
[PubMed]
245.
Dong
H.
,
Wang
S.
,
Zeng
Z.
,
Li
F.
,
Montalvo-Ortiz
J.
,
Tucker
C.
et al.
(
2014
)
Effects of corticotrophin-releasing factor receptor 1 antagonists on amyloid-beta and behavior in Tg2576 mice
.
Psychopharmacology (Berl.)
231
,
4711
4722
[PubMed]
246.
Carroll
J.C.
,
Iba
M.
,
Bangasser
D.A.
,
Valentino
R.J.
,
James
M.J.
,
Brunden
K.R.
et al.
(
2011
)
Chronic stress exacerbates tau pathology, neurodegeneration, and cognitive performance through a corticotropin-releasing factor receptor-dependent mechanism in a transgenic mouse model of tauopathy
.
J. Neurosci.
31
,
14436
14449
[PubMed]
247.
Dong
H.
,
Keegan
J.M.
,
Hong
E.
,
Gallardo
C.
,
Montalvo-Ortiz
J.
,
Wang
B.
et al.
(
2018
)
Corticotrophin releasing factor receptor 1 antagonists prevent chronic stress-induced behavioral changes and synapse loss in aged rats
.
Psychoneuroendocrinology
90
,
92
101
[PubMed]
248.
Lechan
R.M.
and
Jackson
I.M.
(
1982
)
Immunohistochemical localization of thyrotropin-releasing hormone in the rat hypothalamus and pituitary
.
Endocrinology
111
,
55
65
[PubMed]
249.
Guo
F.
,
Bakal
K.
,
Minokoshi
Y.
and
Hollenberg
A.N.
(
2004
)
Leptin signaling targets the thyrotropin-releasing hormone gene promoter in vivo
.
Endocrinology
145
,
2221
2227
[PubMed]
250.
Kim
M.S.
,
Small
C.J.
,
Russell
S.H.
,
Morgan
D.G.
,
Abbott
C.R.
,
alAhmed
S.H.
et al.
(
2002
)
Effects of melanocortin receptor ligands on thyrotropin-releasing hormone release: evidence for the differential roles of melanocortin 3 and 4 receptors
.
J. Neuroendocrinol.
14
,
276
282
[PubMed]
251.
Fekete
C.
,
Kelly
J.
,
Mihaly
E.
,
Sarkar
S.
,
Rand
W.M.
,
Legradi
G.
et al.
(
2001
)
Neuropeptide Y has a central inhibitory action on the hypothalamic-pituitary-thyroid axis
.
Endocrinology
142
,
2606
2613
[PubMed]
252.
Schaner
P.
,
Todd
R.B.
,
Seidah
N.G.
and
Nillni
E.A.
(
1997
)
Processing of prothyrotropin-releasing hormone by the family of prohormone convertases
.
J. Biol. Chem.
272
,
19958
19968
[PubMed]
253.
Trubacova
R.
,
Drastichova
Z.
and
Novotny
J.
(
2022
)
Biochemical and physiological insights into TRH receptor-mediated signaling
.
Front Cell Dev. Biol.
10
,
981452
[PubMed]
254.
Perello
M.
,
Cakir
I.
,
Cyr
N.E.
,
Romero
A.
,
Stuart
R.C.
,
Chiappini
F.
et al.
(
2010
)
Maintenance of the thyroid axis during diet-induced obesity in rodents is controlled at the central level
.
Am. J. Physiol. Endocrinol. Metab.
299
,
E976
E989
[PubMed]
255.
Blake
N.G.
,
Eckland
D.J.
,
Foster
O.J.
and
Lightman
S.L.
(
1991
)
Inhibition of hypothalamic thyrotropin-releasing hormone messenger ribonucleic acid during food deprivation
.
Endocrinology
129
,
2714
2718
[PubMed]
256.
van Haasteren
G.A.
,
Linkels
E.
,
Klootwijk
W.
,
van Toor
H.
,
Rondeel
J.M.
,
Themmen
A.P.
et al.
(
1995
)
Starvation-induced changes in the hypothalamic content of prothyrotrophin-releasing hormone (proTRH) mRNA and the hypothalamic release of proTRH-derived peptides: role of the adrenal gland
.
J. Endocrinol.
145
,
143
153
[PubMed]
257.
Vijayan
E.
and
McCann
S.M.
(
1977
)
Suppression of feeding and drinking activity in rats following intraventricular injection of thyrotropin releasing hormone (TRH)
.
Endocrinology
100
,
1727
1730
[PubMed]
258.
Steward
C.A.
,
Horan
T.L.
,
Schuhler
S.
,
Bennett
G.W.
and
Ebling
F.J.
(
2003
)
Central administration of thyrotropin releasing hormone (TRH) and related peptides inhibits feeding behavior in the Siberian hamster
.
Neuroreport
14
,
687
691
[PubMed]
259.
Nillni
E.A.
(
2010
)
Regulation of the hypothalamic thyrotropin releasing hormone (TRH) neuron by neuronal and peripheral inputs
.
Front. Neuroendocrinol.
31
,
134
156
[PubMed]
260.
Suzuki
T.
,
Kohno
H.
,
Sakurada
T.
,
Tadano
T.
and
Kisara
K.
(
1982
)
Intracranial injection of thyrotropin releasing hormone (TRH) suppresses starvation-induced feeding and drinking in rats
.
Pharmacol. Biochem. Behav.
17
,
249
253
[PubMed]
261.
Morley
J.E.
and
Levine
A.S.
(
1980
)
Thyrotropin releasing hormone (TRH) suppresses stress induced eating
.
Life Sci.
27
,
269
274
[PubMed]
262.
Pierpaoli
W.
and
Lesnikov
V.A.
(
2011
)
Effects of long-term intraperitoneal injection of thyrotropin-releasing hormone (TRH) on aging- and obesity-related changes in body weight, lipid metabolism, and thyroid functions
.
Curr Aging Sci.
4
,
25
32
[PubMed]
263.
Luo
L.
,
Yano
N.
,
Mao
Q.
,
Jackson
I.M.
and
Stopa
E.G.
(
2002
)
Thyrotropin releasing hormone (TRH) in the hippocampus of Alzheimer patients
.
J. Alzheimers Dis.
4
,
97
103
[PubMed]
264.
Horita
A.
,
Carino
M.A.
,
Zabawska
J.
and
Lai
H.
(
1989
)
TRH analog MK-771 reverses neurochemical and learning deficits in medial septal-lesioned rats
.
Peptides
10
,
121
124
[PubMed]
265.
Stocca
G.
and
Nistri
A.
(
1996
)
The neuropeptide thyrotropin-releasing hormone modulates GABAergic synaptic transmission on pyramidal neurones of the rat hippocampal slice
.
Peptides
17
,
1197
1202
[PubMed]
266.
Ren
B.
,
Ma
J.
,
Tao
M.
,
Jing
G.
,
Han
S.
,
Zhou
C.
et al.
(
2023
)
The disturbance of thyroid-associated hormone and its receptors in brain and blood circulation existed in the early stage of mouse model of Alzheimer's disease
.
Aging (Albany NY)
15
,
1591
1602
[PubMed]

Author notes

*

These authors contributed equally to this work.

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