BAT (brown adipose tissue) is the main site of thermogenesis in mammals. It is essential to ensure thermoregulation in newborns. It is also found in (some) adult humans. Its capacity to oxidize fatty acids and glucose without ATP production contributes to energy expenditure and glucose homoeostasis. Brown fat activation has thus emerged as an attractive therapeutic target for the treatment of obesity and the metabolic syndrome. In the present review, we integrate the recent advances on the metabolic role of BAT and its relation with other tissues as well as its potential contribution to fighting obesity and the metabolic syndrome.

INTRODUCTION

Obesity is a status of chronic positive energy balance associated with excess fat storage resulting from energy intake exceeding energy expenditure. Excess fat that first accumulates in adipose tissues and eventually in non-adipose tissues associates with chronic low-grade inflammation and resistance to insulin. Obesity thereby constitutes a major risk factor for the development of Type 2 diabetes, cardiovascular diseases and NAFLD (non-alcoholic fatty liver disease) including steatohepatitis.

Adipose tissue has been traditionally subclassified into WAT (white adipose tissue) and BAT (brown adipose tissue). They play opposing roles, with WAT acting as the main site of metabolic energy storage in the form of TAGs (triacylglycerols), whereas BAT is a specialized thermogenic organ that burns substrates to produce heat during cold or high-calorie diet exposure [1]. In addition, adipocytes expressing thermogenic genes may be present in WAT under specific circumstances. Those are termed brown-like adipocytes (also designated beige or brite adipocytes, and hereinafter referred to as brite adipocytes) [24]. We summarize the main characteristics of white, brite and brown adipocytes in Table 1 and refer the readers to excellent previous publications [510] for detailed information.

Table 1
Main characteristics of white, brite and brown adipocytes

sWAT, subcutaneous white adipose tissue; TCF21, transcription factor 21; TMEM26, transmembrane protein 26; TBX1, T-box 1; EPSTI1, epithelial stromal interaction 1; ZIC1, zinc finger protein of the cerebellum 1; FGF21, fibroblast growth factor 21; BMP, bone morphogenetic protein.

CharacteristicWhite adipocytesBrite adipocytesBrown adipocytes
Location Subcutaneous (sWAT), mesenteric, retroperitoneal, perigonadal, omental Within inguinal WAT, other sWAT? Interscapular, perirenal, axillary, paravertebral 
Morphology Unilocular/large lipid droplets Multilocular/multiple small lipid droplets Multilocular/multiple small lipid droplets 
Origin Adipoblast (Myf5Adipoblast (Myf5Myogenic precursor (Myf5+
Function Energy storage as triacylglycerols Increase energy expenditure Thermogenesis 
UCP1 level Nearly undetectable Basal: low High 
  Stimulated: high  
Mitochondria content Low Medium High 
Correlation with insulin resistance and obesity Positive Negative Negative 
Characteristic markers TCF21 CD137, TMEM26, TBX1, EPSTI1 ZIC1 
Activators High caloric intake (HFD, sugar), low physical activity Cold, thiazolidinediones, natriuretic peptide, FGF21, irisin, catecholamines, β-adrenergic receptor agonists Cold, βAR, thyroid hormone, FGF21, thiazolidinediones, BMP7, BMP8B, natriuretic peptide 
    
CharacteristicWhite adipocytesBrite adipocytesBrown adipocytes
Location Subcutaneous (sWAT), mesenteric, retroperitoneal, perigonadal, omental Within inguinal WAT, other sWAT? Interscapular, perirenal, axillary, paravertebral 
Morphology Unilocular/large lipid droplets Multilocular/multiple small lipid droplets Multilocular/multiple small lipid droplets 
Origin Adipoblast (Myf5Adipoblast (Myf5Myogenic precursor (Myf5+
Function Energy storage as triacylglycerols Increase energy expenditure Thermogenesis 
UCP1 level Nearly undetectable Basal: low High 
  Stimulated: high  
Mitochondria content Low Medium High 
Correlation with insulin resistance and obesity Positive Negative Negative 
Characteristic markers TCF21 CD137, TMEM26, TBX1, EPSTI1 ZIC1 
Activators High caloric intake (HFD, sugar), low physical activity Cold, thiazolidinediones, natriuretic peptide, FGF21, irisin, catecholamines, β-adrenergic receptor agonists Cold, βAR, thyroid hormone, FGF21, thiazolidinediones, BMP7, BMP8B, natriuretic peptide 
    

The literature largely documents the role of WAT in obesity and diabetes and the noxious contribution of altered lipid metabolism and partitioning, chronic inflammation and production of endocrine mediators to systemic metabolic disturbances. In the present review, we focus on the metabolic role of BAT and compile available data to address the following questions: are BAT and brite adipocytes relevant therapeutic targets in obesity? What are the means to stimulate BAT and browning of adipose depots? Would stimulation of BAT or brite adipocyte activity effectively combat obesity and the metabolic syndrome?

BAT can be found during the entire lifespan in hibernators and some small mammals (e.g. mice and rats). Newborn lambs and other precocious mammals have large amounts of BAT, but it is only found in small amounts in newborn humans, where it probably serves to counteract heat loss associated with the abrupt change to the extra-uterine environment. With increasing age, as the rate of heat loss per unit body weight decreases, the tissue decreases and could become indistinguishable in aspect and function from white fat [11]. However, over the last decade, experiments using CT (computed tomography) scanning combined with 18F-FDG (2-[18F]fluoro-2-deoxy-D-glucose)-PET (positron emission tomography) identified significant amounts of functional BAT in (some) adult humans: it is mainly located at the base of the neck and is metabolically activated upon cold exposure [1215]. Recent studies have been aimed at evaluating the contribution of activated BAT to the basal metabolic rate. The average BAT mass of a healthy adult is estimated to be approximately 50 g and to contribute to 3–5% of the basal metabolic rate [15,16]. As an example, in a subject with 63 g of supraclavicular BAT, it was calculated that, if the depot was fully activated, it would burn an amount of energy equivalent to 4.1 kg of WAT (or 38500 kcal; 1 kcal=4.184 kJ) over the course of 1 year [15]. This represents the energy needed to cover the resting metabolism for 20 days. Thus the stimulation of BAT in humans can potentially increase the total daily energy expenditure and conceptually becomes a target to treat obesity.

METABOLISM AND ACTIVATION OF BAT

Brown adipocytes are rich in mitochondria and are characterized by high expression and inducibility of UCP1 (uncoupling protein 1), enabling BAT to transform energy stored as TAG into heat. UCP1, a fatty acid anion–H+ symporter acids [17], uncouples mitochondrial oxidative phosphorylation by bypassing the electrochemical gradient across the inner mitochondrial membrane from ATP synthase and thereby dissipates energy as heat. The prevailing role of UCP1 in BAT-mediated thermogenesis is exemplified in mice genetically lacking UCP1: UCP1−/− mice displayed an impaired ability to produce heat by non-shivering thermogenesis and exhibited cold intolerance [18]. Also UCP1-null mice have been reported to gain more body weight than wild-type controls when housed at thermoneutral temperature [19].

NEFAs [non-esterified (‘free’) fatty acids] are the main substrates for combustion and are essential for proper function and energy expenditure of brown adipocytes. FA (fatty acid) uptake in adipocytes is mainly regulated by the FA translocase CD36, as well as by specific isoforms of FATPs (fatty acid transport proteins), including FATP1 and FATP4 [20]. Once inside the cell, FAs may either be stored as TAG in lipid droplets or transported into the mitochondria for oxidation. The functional capacity of BAT relies on NEFA availability. Indeed, mice lacking CD36 or FATPs are unable to survive the cold due to lack of availability of fats for combustion in brown fat thermogenesis [21,22]. Also, a lack of ATGL (adipose triacylglycerol lipase), the enzyme that catalyses the initial step in TAG hydrolysis renders the mice profoundly cold-intolerant [23]. Bartelt et al. [21] showed that a short-term cold exposure drastically accelerated plasma clearance of TAG as a result of increased uptake into mouse BAT, a process crucially dependent on local lipoprotein lipase activity and transmembrane receptor CD36.

Besides NEFAs, BAT also uses glucose as a substrate during thermogenesis, particularly under sympathetic activation [24]. Interestingly, BAT glucose uptake is as high as uptake by human metastatic cancer cells [25]. Glucose that is not immediately oxidized may accumulate as glycogen [26] and ultimately be converted into lipids to replenish the TAG droplets. Fasting serum glucose concentrations are lower in individuals with detectable BAT than in those without detectable BAT [27], which implies that glucose uptake by metabolically active BAT might directly affect blood glucose concentrations in human beings. BAT is able to uptake glucose by an insulin-independent or an insulin-dependent way. Orava et al. [28] showed that, in healthy subjects, glucose uptake after cold exposure increased 12-fold in BAT, and was correlated with an increase in whole-body energy expenditure, whereas insulin-stimulated glucose uptake in BAT increased only 5-fold. Interestingly, upon cold exposure, gene expression of GLUT4 (glucose transporter 4) was higher in BAT than in WAT in these subjects. Moreover, in mice, the expression of GLUT1, GLUT4 and lipoprotein lipase in BAT was higher than in any other tissues after cold exposure [21,24,29]. A high vascularization is essential for supplying BAT with substrates and oxygen and transporting the generated heat to the rest of the body [24,29,30].

The SNS (sympathetic nervous system) is the single most important regulator of BAT function and regulates dynamic changes as well as prolonged adaptation [24]. Upon cold exposure, catecholamines [in particular, noradrenaline (norepinephrine)] released by the sympathetic nerves act on adrenergic receptors in BAT and activates adenylate cyclase to increase intracellular cAMP levels, which then trigger activation of PKA (cAMP-dependent protein kinase). In turn, PKA phosphorylates hormone-sensitive lipase leading to the hydrolysis of TAG into NEFAs, the main substrate for heat production in BAT. Long-chain NEFAs induce UCP1 to uncouple mitochondrial oxidative phosphorylation from ATP synthesis and dissipate the energy as heat [24].

Noradrenaline, the main regulator of non-shivering thermogenesis, activates βARs (β-adrenergic receptors). All three βAR isoforms are expressed in BAT [31]. Targeted disruption of all three isoforms, β1AR, β2AR and β3AR, in mice provokes cold-induced hypothermia as well as diet-induced obesity [32,33]. β3AR is preferentially expressed in BAT and is therefore suggested to play a major role in thermogenesis. However, β3KO (β3AR-knockout) mice have no significant defect in basal metabolic rate, adaptive response to cold exposure [34] or metabolic response to diet-induced obesity [35]. It was proposed that, in these mice, the absence of β3AR was compensated for by up-regulation of β1ARs that allow them to survive in cold [36,37]. Some studies have indicated that the β1AR is key for BAT thermogenesis [37] as β1KO (β1AR-knockout) mice, with functional β3AR, develop hypothermia when exposed to cold as well as obesity in response to an HFD (high-fat diet) [38]. The role played by β2AR is still unclear. Stimulation of β2AR with salbutamol accelerates energy expenditure, lipolysis and fat oxidation without affecting glucose oxidation in humans [39]. However, β2KO (β2AR-knockout) mice maintain their thermogenic adaptation, probably due to increased expression of β1AR and β3AR mRNAs in their BAT [40].

Confirming the major activating role of the sympathetic system in humans, non-specific βAR blockers completely inhibit the BAT signals during 18F-FDG-PET–CT [41]. Although β2AR is the most abundant isoform at the transcript level in human BAT, β3AR mRNA is predominately found in brown and white adipocytes [42], and not or only negligibly in other tissues. In addition, β3AR induction is also implicated in the browning of WAT [43]. Therefore it is tempting to speculate that highly selective β3AR agonists (not yet available) would stimulate energy expenditure without unwanted side effects. All being considered, the magnitude of adrenergic activation of BAT is likely to rely on an intricate balance between total and relative abundance of membrane receptor isoforms, concentration and affinity of ligands in loco, and operation of sensitizers of receptor-induced signal (see below) [4446].

The concept of ‘diet-induced thermogenesis’ emerged from experiments in the 1970s when Rothwell and Stock [47] observed that overfed rats gained less weight than expected from excess caloric intake and increased their oxygen consumption and BAT mass. They proposed that unaccounted calories were burned off by the induction of BAT thermogenesis [47]. However, this explanation was questioned by other studies. Ma et al. [48] showed that, in rats fed on a cafeteria diet, enhanced metabolism was not associated with a particular increase in oxygen consumption by BAT. This conclusion has been corroborated in a study showing a comparable increase in whole body oxygen consumption in UCP1+/+ and UCP1−/− mice when the diet is switched from chow to high fat/high sucrose [49], indicating that diet-induced enhanced metabolism is independent of UCP1 expression. Contradictorily, Feldmann et al. [19] demonstrated that UCP1-knockout mice housed at thermoneutrality have greater weight gain on an HFD than wild-type mice, suggesting a role for BAT in diet-induced obesity [19]. Our data also support the notion of diet-induced thermogenesis: when WT mice are fed on an HFD, we observed an induced expression of thermogenic genes encoding UCP1, PGC1α [PPARγ (peroxisome-proliferator-activated receptor γ) co-activator 1] and DIO2 (type II iodothyronine deiodinase) and an increased number of mitochondria per brown adipocyte, suggesting an adaptation of the mice to counteract the excess of dietary fat intake [50]. Recently, Zhang et al. [51] showed that the administration of medium-chain TAGs to mice stimulated the activation of BAT, possibly via the noradrenaline pathway. In humans, overfeeding leads to an increase in sympathetic activity [52,53] and increases total daily energy expenditure [54]. This is paralleled by elevation in skin temperature relative to baseline indicating extra dissipation of heat to the environment [54,55]. However, the contribution of enhanced brown adipose metabolism has not been established.

BROWNING OF WAT: BRITE ADIPOCYTES

Browning of WAT can be seen as the emergence, within white adipose pads, of adipocytes with thermogenic properties, i.e. uncoupling and heat production capacities enabling enhanced lipolysis. The process of browning has only partially been elucidated, but appears to be controlled by circulating and hormonal factors reflecting the energy, metabolic and nutritional status, the level of physical activity or the response to external cold temperature, all factors known to also activate BAT. A number of positive and negative regulators of brown and brite adipocyte development have been identified, as summarized in Table 2. The potential anti-obesity properties of browning are supported by experiments in mice with selective ablation of brite adipose cells. These mice are prone to obesity and metabolic dysfunction, particularly hepatic insulin resistance [56], probably by reducing lipogenic capacity and energy expenditure as well as modulating the local and inflammatory environment inside the white adipose depots. Moreover, mice overexpressing Prdm16 (PR domain-containing 16), a key gene in browning, developed abundant brite adipocytes in the subcutaneous adipose tissue associated with an increased energy expenditure, a limited weight gain and an improved glucose tolerance in response to an HFD [57]. In humans, evidence of fat browning was first shown in patients with phaeochromocytoma, a condition associated with unrestrained production of catecholamines [58]. Brite adipocytes can also be found scattered in WAT after cold exposure [59], treatment with βAR agonists [60] or with PPARγ agonists [61]. Further studies are needed to determine the contribution of these brite adipocytes to improved metabolism and whether their therapeutic targeting would be effective to combat obesity and dysmetabolic conditions.

Table 2
Browning of WAT

PGC1α, PPARγ co-activator 1α; IL, interleukin; BMP, bone morphogenetic protein; FGF, fibroblast growth factor; GDF5, growth differentiation factor-5; VEGF, vascular endothelial growth factor; BAIBA, β-aminoisobutyric acid; BDNF, brain-derived neurotrophic factor; PTHrP, tumour-derived parathyroid hormone-related protein; PRDM16, PR domain-containing 16; EHMT1, euchromatic histone-lysine N-methyltransferase 1; C-EBPβ, CCAAT/enhancer-binding protein β; PPARγ, peroxisome-proliferator-activated receptor γ; TGFβ, transforming growth factor β; TNFα, tumour necrosis factor α; Aldh1, retinaldehyde dehydrogenase 1; RIP140, receptor-interacting protein 140; LXRα, liver X receptor α; VDR, vitamin D receptor; Cidea, cell death-inducing DFFA-like effector A; pRB, retinoblastoma protein; TRPV4, transient receptor potential vanilloid 4; 4E-BP1, eukaryotic translation initiation factor 4E-binding protein 1; TFAM, mitochondrial transcription factor A.

MediatorsReference(s)
Induction by   
 Chronic exercise ↑ PGC1α that up-regulates irisin and meteorin-like in skeletal muscle [94
 ↑ IL-6 [84,166
 Lactate? [167
 Chronic cold exposure ↑ IL-4/IL-13 leading to ↑ meteorin-like in BAT and WAT and secretion of catecholamines by M2 macrophages in WAT [111,112
 Endocrine hormones and metabolites BMP4, BMP7, BMP8b, FGF19, FGF21 [76,104,168170
 GDF5, natriuretic peptides, prostaglandins [95,126,171
 VEGF, BAIBA [172,173
 Enriched environment BDNF [174
 Cancer cachexia IL-6 [175
 PTHrP [176
 Transcriptional mediators PRDM16, EHMT1, C-EBPα, PPARγ, PGC1α,… [162,177181
 Drugs? β3AR agonist CL316,243 and others [43,182
   
Inhibition by   
 Obesity ↑ TGFβ [183
 ↑ Inflammation (TNFα…) [184
 ↑ Aldh1 (retinoic acid) [185
 Inhibition of Notch signalling [186
 Transcriptional mediators RIP140 [187189
 LXRα [190,191
 VDR [192,193
 Cidea [194
 pRB and p107 [195
 TRPV4 [196
 4E-BP1 [197
 TFAM [198
MediatorsReference(s)
Induction by   
 Chronic exercise ↑ PGC1α that up-regulates irisin and meteorin-like in skeletal muscle [94
 ↑ IL-6 [84,166
 Lactate? [167
 Chronic cold exposure ↑ IL-4/IL-13 leading to ↑ meteorin-like in BAT and WAT and secretion of catecholamines by M2 macrophages in WAT [111,112
 Endocrine hormones and metabolites BMP4, BMP7, BMP8b, FGF19, FGF21 [76,104,168170
 GDF5, natriuretic peptides, prostaglandins [95,126,171
 VEGF, BAIBA [172,173
 Enriched environment BDNF [174
 Cancer cachexia IL-6 [175
 PTHrP [176
 Transcriptional mediators PRDM16, EHMT1, C-EBPα, PPARγ, PGC1α,… [162,177181
 Drugs? β3AR agonist CL316,243 and others [43,182
   
Inhibition by   
 Obesity ↑ TGFβ [183
 ↑ Inflammation (TNFα…) [184
 ↑ Aldh1 (retinoic acid) [185
 Inhibition of Notch signalling [186
 Transcriptional mediators RIP140 [187189
 LXRα [190,191
 VDR [192,193
 Cidea [194
 pRB and p107 [195
 TRPV4 [196
 4E-BP1 [197
 TFAM [198

BROWN ADIPOCYTES: PART OF A MULTI-ORGAN CROSS-TALK

The literature increasingly recognizes that BAT is part of a multi-organ network that controls energy homoeostasis and dissipation and energy substrate utilization. As represented schematically in Figure 1, on the one hand BAT releases circulating factors such as FGF21 (fibroblast growth factor 21), IL (interleukin)-6 and IGF-1 (insulin-like growth factor 1) able to modulate sympathetic tone, FA oxidation and glucose uptake thorough the body (Figure 1A and Table 3); on the other hand, factors such as the sympathetic tone, neuropeptides, pancreatic and thyroid hormones, cardiac natriuretic peptides or other muscle-derived factors may directly modulate substrate consumption and activity of thermogenic adipocytes (Figure 1B).

Central role of BAT in inter-organ cross-talk

Figure 1
Central role of BAT in inter-organ cross-talk

(A) BAT as an endocrine organ. BAT releases circulating factors such as FGF21, IL-6, T3 and IGF-1, able to activate the SNS. FA oxidation improves glucose homoeostasis. (B) Brown fat formation and thermogenic activity can be modulated by secreted factors from several organs. As shown in green, bile acids, FGF21, adipokines, cardiac natriuretic peptides, pancreatic and thyroid hormones, noradrenaline (NE), irisin and meteorin-like from muscle improve BAT function and/or induce the browning of WAT. NPY and serotonin inhibit these pathways (in red). Changes due to obesity are indicated by a red arrow.

Figure 1
Central role of BAT in inter-organ cross-talk

(A) BAT as an endocrine organ. BAT releases circulating factors such as FGF21, IL-6, T3 and IGF-1, able to activate the SNS. FA oxidation improves glucose homoeostasis. (B) Brown fat formation and thermogenic activity can be modulated by secreted factors from several organs. As shown in green, bile acids, FGF21, adipokines, cardiac natriuretic peptides, pancreatic and thyroid hormones, noradrenaline (NE), irisin and meteorin-like from muscle improve BAT function and/or induce the browning of WAT. NPY and serotonin inhibit these pathways (in red). Changes due to obesity are indicated by a red arrow.

BAT as an endocrine organ

In vitro studies revealed that brown adipocytes stimulated with noradrenaline release IL-1α, IL-6 [62], leptin [63,64] and FGF21 [65]. BAT transplantation experiments strongly support that the tissue produces endocrine signals. Metabolic improvement upon BAT transplantation is also and perhaps predominantly due to functional changes in endogenous tissues (including BAT and WAT) rather than to the thermogenic capacity brought by the transplanted cells [66]. Subcutaneous transplantation of embryonic BAT normalized glucose levels and reversed diabetes symptoms in rodent models of streptozotocin-induced diabetes (Type 1) [67,68]. The authors proposed that BAT-released IGF-1 acts as an endocrine factor mimicking the actions of insulin in ameliorating diabetes. Another study conducted by Stanford et al. [69] reported that BAT transplantation into mice improved glucose tolerance and insulin sensitivity, and decreased fat mass. Because glucose uptake was increased in peripheral tissues, including WAT and the heart, they hypothesized that paracrine and endocrine mechanisms mediated the antidiabetic effects of BAT transplantation. BAT transplantation was associated with a sustained secretion of FGF21 and IL-6 from the transplanted tissue [69], but BAT from IL-6-null mice neither improves the metabolic status of mice nor induces an FGF21 increase, supporting that FGF21, secreted in a IL-6-dependent fashion, could be an endocrine factor responsible for mediating the effects of BAT. Indeed, FGF21 acts both centrally, to stimulate sympathetic outflow and energy expenditure [70], and on BAT, to increase glucose uptake and substrate mobilization [71,72]. Nevertheless, in a subsequent experiment, phenotypic improvement of ob/ob mice in response to BAT transplantation was found to occur in the absence of change in FGF21 circulating levels [66]. BAT can also release thyroid hormone T3 (tri-iodothyronine) [73]. Locally generated T3 contributes to the intracellular pathways of thermogenic activation [74]. Whether it also has hormone properties outside the organ has not been demonstrated. Central administration of T3 in rats leads to SNS activation and up-regulation of BAT thermogenesis [75]. Another major BAT-released factor, BMP8B (bone morphogenetic protein 8B), induced by nutritional and thermogenic factors in mature BAT, was shown to increase the sensitivity to noradrenergic action. Central administration of BMP8B to rodents induced thermogenesis and increased core temperature, leading to weight loss [76].

Sympathetic nervous system

Catecholamines released by the SNS in response to cold exposure or to excess energy load operate a critical control on BAT thermogenesis. Several other neuropeptides and hormones have been linked to thermogenic activity: orexin promotes brown fat development during gestational growth [77], NPY (neuropeptide Y) [78] and serotonin [79] inhibit thermogenesis by blunting β-adrenergic induction. Interestingly, obesity is associated with low levels of orexin and high levels of NPY [80] and serotonin [79]

Muscle

IL-6 is predominantly known as a pro-inflammatory cytokine as well as an adipokine produced by overloaded and inflamed WAT, including BAT [81,82]. IL-6 is also a myokine released by the exercised skeletal muscle [83]. As reported above, it could serve as upstream stimulus for FGF21 production by BAT, although the contribution of muscle-derived IL-6 in the process has not been established. IL-6 has also been shown to activate brite adipocyte development and to be required for exercise-induced WAT browning in mice [84]. Irisin is a myokine obtained by cleavage from the precursor protein FNDC5 (fibronectin type III domain-containing 5) expressed by skeletal muscles and perhaps to a greater extent by cardiac muscle [85]. In cell culture, FNDC5/irisin promotes the browning of WAT. In mice in vivo, recombinant FNDC5/irisin induces the PGC1α pathway and the expression of a brite adipocyte gene signature in an autonomous manner [86,87]. Interestingly, physical exercise induces the release of FNDC5/irisin by skeletal muscle in rodents [88,89]. However, initial data in rodents do not translate to humans [9092]. Indeed, in a majority of studies, circulating FNDC5/irisin concentrations did not significantly change upon acute exercise or prolonged physical training [9093]. Other myokines, such as meteorin-like [94], have been proposed as possible regulators of browning. However attractive the idea that the trained muscle may contribute to enhanced thermogenic activity in BAT and WAT via the release of myokines and thereby to a better control of energy homoeostasis, more investigations are required to demonstrate the operation of muscle-derived factors, to identify the factors at play and their regulation by physical exercise in healthy human beings as well as in patients suffering obesity, the metabolic syndrome or Type 2 diabetes.

Heart

Cardiac ANP (atrial natriuretic peptide) and BNP (brain natriuretic peptide) were originally identified as important in blood pressure control. Almost 20 years ago, receptors for ANP and BNP were found in human adipose tissue. Natriuretic peptides stimulate lipolysis but also activate brown adipocytes, and are involved in the browning of white adipocytes by increasing mitochondrial biogenesis and uncoupled respiration [95,96]. Interestingly, obesity is associated with a reduction in plasma levels of natriuretic peptides [97]. In contrast, cold exposure [95] or chronic exercise [98,99] increased the release of ANP and BNP by the heart.

Table 3
Main factors produced by the BAT under stimulus (cold, noradrenaline) and their role

BMP8B, bone morphogenetic protein 8b; FGF, fibroblast growth factor; IL, interleukin; T3, tri-iodothyronine; IGF-1, insulin-like growth factor 1; VEGF-A, vascular endothelial growth factor A; RBP4, retinol-binding protein-4; PTGDS, prostaglandin D2 synthase.

FactorMain roleAutocrine (A), paracrine (P) or endocrine (E)?Reference(s)
BMP8B Increase the sensitivity and amplify the response of brown adipocytes to adrenergic stimulation A/P/E [76
FGF21 Act on the brain to increase hepatic insulin sensitivity and metabolic rate A/E [199
 Also released by beige brite adipocytes  [72,200
IL-6 Inflammation A/P/E [69
 Improve insulin sensitivity  [201
T3 Contribute to the intracellular pathways of thermogenic activation of brown adipocytes A/E [73,75,202
IGF-1 Increase the density of brown adipocyte precursor cells A/E [203
FGF2 Brown adipocyte precursor increase [204
Angiotensinogen Increase noradrenaline release? A/P [24
IL-1α Inflammation A/P [62
VEGF-A Increase vascularization in BAT [205
 Up-regulate UCP1 and PGC1α in BAT   
RBP4 Unknown A/P/E [206
PTGDS Prostaglandin synthesis A/E [207
 Carrier of lipophilic molecules   
FactorMain roleAutocrine (A), paracrine (P) or endocrine (E)?Reference(s)
BMP8B Increase the sensitivity and amplify the response of brown adipocytes to adrenergic stimulation A/P/E [76
FGF21 Act on the brain to increase hepatic insulin sensitivity and metabolic rate A/E [199
 Also released by beige brite adipocytes  [72,200
IL-6 Inflammation A/P/E [69
 Improve insulin sensitivity  [201
T3 Contribute to the intracellular pathways of thermogenic activation of brown adipocytes A/E [73,75,202
IGF-1 Increase the density of brown adipocyte precursor cells A/E [203
FGF2 Brown adipocyte precursor increase [204
Angiotensinogen Increase noradrenaline release? A/P [24
IL-1α Inflammation A/P [62
VEGF-A Increase vascularization in BAT [205
 Up-regulate UCP1 and PGC1α in BAT   
RBP4 Unknown A/P/E [206
PTGDS Prostaglandin synthesis A/E [207
 Carrier of lipophilic molecules   

Liver

Administration of bile acids (the natural cholic acid or a semi-synthetic cholic acid derivative, INT777) further enhanced HFD-induced thermogenesis and UCP1 up-regulation in BAT [100,101]. The effects of bile acids are mediated by their binding to the membrane receptor TGR5 (G-protein-coupled bile acid receptor 1) [102]. Activation of TGR5 leads to an increase in DIO2 activity that converts T4 (thyroxine) into T3. T3 is predicted to induce UCP expression enhancing the thermogenic programme [100,103]. Besides producing and regulating the bile acid pool that may influence the TGR5 tone, the liver is also the major organ producing FGF21 [104106]. Selective overexpression of FGF21 in the liver prevents HFD-induced obesity, insulin resistance and fatty liver [71]. This effect is associated with increased expression of genes involved in adaptive thermogenesis in BAT, but also in WAT [71]. In addition, Markan et al. [107] showed that liver-derived FGF21 acts as an insulin sensitizer and improves glucose uptake including in BAT [107].

Macrophages

Catecholamines sensitize macrophages and other inflammatory cells to produce pro-inflammatory cytokines [108,109]. Some studies have investigated the possibility of catecholamine production by alternatively activated macrophages [110], whose presence in BAT [111] and WAT [112] coincides with adaptation to low temperature. Supporting that alternatively polarized macrophages influence lipolytic and thermogenic activity of the tissue, the absence of such M2 macrophages caused impaired metabolic adaptation to cold [111]. Conditions promoting such immune polarization, resulting in the contribution of in situ produced catecholamines to brown and brite cell function and the relevance of such a mechanism to energy dissipation remains to be established, particularly in human subjects.

Thyroid

The thyroid gland mainly secretes the inactive pro-hormone T4 which is taken up by brown adipocytes and converted into the active thyroid hormone (T3) by DIO2 following sympathetic stimulation [113]. In rodents, it is well known that thyroid hormone enhances BAT thermogenesis [75,114,115]. In humans, the effect of thyroid hormone on BAT was demonstrated in a case report of a diabetic patient with resected thyroid. Thyroid hormone replacement was accompanied with activation of BAT on 18F-FDG PET–CT [116]. Recently, Lombardi et al. [117] showed that hypothyroidism suppresses the maximal oxidative capacity of BAT and thermogenesis, and in vivo administration of T2, a thyroid hormone derivative, to hypothyroid rats activated BAT thermogenesis by increasing UCP1 and PGC1α expression.

Pancreas

The pancreas is the main production site for glucagon and insulin. Brown adipocytes bear glucagon receptors [118]. Plasma glucagon levels increase upon cold exposure in both rats and humans [119], probably as a result of a cold-induced increase in catecholamine concentration [120]. When glucagon was given to cold-acclimatized rats, BAT activity was potentiated [121]. Exposure of brown adipocytes of rats and mice to glucagon, but not those of Syrian hamsters, markedly increased oxygen consumption. However, the concentrations of glucagon required for such effects have been speculated to be supraphysiological [122]. Besides, the pancreatic hormone insulin is a major regulator of brown adipocyte formation and function as insulin stimulates BAT glucose uptake. The role of the insulin signalling cascade in brown adipogenesis is well established and loss of insulin receptor in BAT has detrimental effects on BAT function [123] that can lead to glucose intolerance [124].

White adipose tissue

Upon sympathetic activation, white adipocytes release PGE2 (prostaglandin E2) and PGI2 (prostaglandin I2 or prostacyclin), synthesized by COXs (cyclo-oxygenases). Acute treatment of primary stromal vascular fraction cells from WAT with these prostaglandins led to an increase in UCP1 and PGC1α expression, driving browning [125]. Simultaneously, Madsen et al. [126] observed that induction of UCP1 expression in inguinal WAT (but not in BAT) is dependent on COX activity and PGE2. White adipocytes are known to release leptin, which could also be involved in thermogenesis. Although both UCP1−/− and ob/ob (leptin-deficient) mice can survive in cold temperatures, when gradually lowering to 4°C, mice lacking both UCP1 and the ob gene could not adapt and survive at temperatures lower than 12°C unless they were administered leptin [127]. This supports the hypothesis that leptin is required for UCP1-independent thermogenesis during cold exposure. Indeed, leptin increased T3 production and, when treated with T3, ob/ob UCP1−/− mice were able to maintain body temperature upon gradual cooling of ambient temperature [127,128]. In addition, stressed white adipocytes have been described to produce catecholamines [129,130], the contribution of which to browning has not been established.

BENEFICIAL EFFECT OF BAT ACTIVATION IN THE METABOLIC SYNDROME

The high capacity of BAT for both glucose and lipid oxidation makes this tissue a potential target for management of the metabolic syndrome: decreased plasma glucose and increased energy expenditure, and thus lowering the risks of obesity and Type 2 diabetes could be expected.

Obesity

Animal and human data support a role for BAT thermogenesis in energy homoeostasis. Lowell et al. [131] developed transgenic mice with primary deficiency of BAT. These mice are characterized by reduced energy expenditure, obesity in the absence of hyperphagia, and insulin resistance [132]. In humans, dedicated studies showed a strong negative correlation between BAT activity (measured by PET–CT) and fat mass and body mass index [12,14,133]. Also, a low body temperature (which could reflect low basal metabolic rate and/or low thermogenesis) is associated with an increased risk of obesity [134,135]. Van Ooijen et al. [136] showed that, during cold exposure, non-shivering thermogenesis in winter is significantly higher compared with summer, in the same volunteers. Moreover, subjects without BAT activity show significantly lower non-shivering thermogenesis [133,137].

Type 2 diabetes

Activating BAT is an attractive strategy to improve glucose homoeostasis, particularly in the context of Type 2 diabetes, in which insulin-activated signalling pathways are compromised. Indeed, the uptake of oxidative substrates by BAT and the activation of thermogenesis in response to sympathetic stimulation is an insulin-independent process [138]. Interestingly, BAT and β-cell functions appear to be linked. Guerra et al. [124] showed that BAT-specific insulin receptor-knockout mice, beyond the age of 6 months, besides developing BAT atrophy have a reduced percentage of β cell mass, and a significant decrease in basal and stimulated insulin secretion causing glucose intolerance. Mechanisms responsible for such an effect, however, remain unidentified.

BAT avidly takes up glucose. Retrospective cohort studies suggest an association between decreased 18F-FDG uptake by BAT and high blood glucose levels [27,139,140]. This association is reinforced by the observation that glucose uptake per BAT volume is lower in diabetic patients than in healthy volunteers [141]. In healthy subjects with active BAT, cold exposure increased resting energy expenditure, plasma glucose oxidation, whole-body glucose disposal, and insulin sensitivity [142]. Similarly, β3AR agonist treatment [138,143145] or BAT transplantation [66,69] in mice also improve glucose tolerance and insulin sensitivity.

NAFLD (non-alcoholic fatty liver disease)

Little is known about the links between BAT activity and the liver. Yilmaz et al. [146] showed that subjects without BAT activity had a significantly higher risk of NAFLD. They also demonstrated that BAT activity was inversely correlated with the degree of liver steatosis and the BMI (body mass index) [146]. In another study, in mice, BAT activation upon short-term cold exposure was associated with the correction of hyperlipidemia by increasing TAG clearance. Interestingly, it seems that hepatic TAG uptake was reduced, indicating that cold exposure may shift the clearance of lipoproteins from liver to BAT [21]. Whether BAT induction could prevent steatosis and its complications remains to be investigated.

TARGETING BAT AS A THERAPEUTIC APPROACH TO TREAT OBESITY AND THE METABOLIC SYNDROME IN HUMANS

The growing prevalence of obesity and associated clinical burden reinforces the urge for therapeutic management. As reviewed above, data in animals support the concept that stimulation of BAT enables increased energy substrate consumption and may confer protection against obesity, insulin resistance and the metabolic syndrome. The ‘rediscovery’ of active and inducible BAT in (at least some) human adults, the demonstration of browning of WAT and the inverse correlation between BAT activity and obesity, together with better understanding of regulatory mechanisms and drug discovery, open new possibilities for therapeutic approaches. In this section, we review available clinical data supporting the concept and identify the need for further investigation.

Sympathetic nervous system activation

Activation of BAT in human subjects is clearly demonstrated using cold exposure experiments. Interestingly, a positive effect on increased BAT metabolic function is obtained with mild protocols as 2 h of exposure to a 19°C ambient temperature with legs lying on an ice block was sufficient to increase 18F-FDG uptake in the supraclavicular regions of patients [12]. Repeated exposure to an ambient temperature of 17°C for 2 h a day for 6 weeks was reported to induce an increase in BAT volume and metabolism and, in responding subjects, to reduce fat mass [147]. Noteworthy, those effects were reported in only 50% of the subjects tested even if they were young and non-obese. With this in mind, selection of patients with ‘active’ BAT or monitoring early response may help to identify potentially BAT-responsive subjects to be enrolled into clinical trials. Another point is that, in responsive subjects, BAT activation was not associated with a reduction in body weight. Obviously, this should be investigated further by long-term protocols. Cold exposure is known to increase appetite and food intake in rodents [148]. The consequences of ‘cold-exposure protocols’ on food consumption, which could mitigate beneficial metabolic effects, has not been evaluated in available human studies. In addition, the repercussions of BAT activation on total energy balance, glucose homoeostasis and insulin sensitivity remain to be addressed experimentally.

Besides protocols of cold exposure, stimulation of the β3AR has attracted a lot of interest and hope in the field of anti-obesity treatment. β3AR stimulation leads to BAT activation and browning, and concurrently to enhanced energy expenditure and reduced food intake in mice studies [149]. In patients with phaeochromocytoma, a correlation between magnitude of BAT activation and plasma total metadrenaline (metanephrine) levels was shown [150]. However, several reports and observations mitigated the initial interest for a β3AR agonist approach in humans. (i) Infusion of isoprenaline (isoprotenerol) (a β1AR, β2AR and β3AR triple agonist) was not able to induce thermogenic capacity or lipid use [151], nor was ephedrine (a sympathomimetic drug with both αAR and βAR agonist properties) able to increase 18F-FDG uptake in BAT unlike cold exposure [152]. (ii) Even more selective β3AR agonists such as CL316,243 [153] or L-796568 [154] had little [153] or no [154] effect on human BAT. (iii) In the absence of high β3AR selectivity, undesirable effects are expected from βAR stimulation in other organs such as the heart and blood vessels [44,46]. In addition to direct inotrope-positive effects of non-selective β3AR agonists, stimulation of BAT could result in cardiac stress from increased energy and oxygen demand and increased need for heat dissipation. Agonist drugs with high selectivity and high affinity for β3AR and improved pharmacokinetic profile are awaited to re-evaluate the potential effect on BAT activation, obesity and metabolism. Alternatively, BAT may be resistant to β3AR stimulation. As reported by Crane et al. [79], serotonin found in excess in the serum of obese patients blunts βAR induction of the thermogenic programme. Restoring of βAR sensitivity or inhibiting serotonin signalling in BAT may prove more effective. As well as β3AR specificity or resistance issues, it is also possible that the BAT mass is too low in humans for its activation to result in an appreciable metabolic effect [45]. As mentioned above, it may therefore be useful to select patients with BAT for clinical evaluation.

Other strategies to activate BAT

In human cohorts, the activity of BAT has been found to be inversely correlated with BMI [12], but whether this is a cause or a consequence of obesity remains unknown. In the same way, we do not know whether weight loss will restore to previously obese humans a functional BAT. If so, a ‘two-step’ therapeutic strategy could be imagined with, first, weight loss and, secondly, BAT-specific targeting. This could be interesting in the light of the relatively low long-term compliance to and benefit of diet, exercise and behavioural weight loss strategies in adults [155].

DNP (2,4-dinitrophenol) is classified as a chemical non-specific uncoupler. It has been used to treat obesity in the 1930s [156]. Although causing increased energy expenditure, it appears to reduce BAT activity [157] and has been shown to cause severe side effects including hyperthermia and risk of death. It is not recommended for human use. Despite this, the product is readily available through the Internet and online pharmacies as a weight loss agent [158].

Thyroid receptor activation has thermogenic properties similar to β3AR activation. However, owing to the potential saturation of the thyroid hormone receptor on BAT [114] and the other general potential side effects of hyperthyroidism, thyroid hormone replacement therapy could not be advised in order to stimulate BAT in humans.

As shown previously, FGF21 is considered as an important activator of brown and brite adipocytes as well as a mediator of pleiotropic beneficial metabolic effects. In obese rodents, FGF21 administration reduces body weight, adiposity and blood glucose [159]. It induces heat production in human adipocytes [89], but data pertaining to systemic administration in vivo are not yet available.

The bile acid receptor TGR5 has emerged as a promising target for metabolic disorders, including obesity, Type 2 diabetes and co-morbidities. TGR5 activation induces the intestinal release of the incretin GLP-1 (glucagon-like peptide-1) [100,101], has anti-inflammatory properties and increases energy expenditure in BAT [100,160]. In humans, TGR5 is expressed in WAT and BAT, and the level of expression is correlated with obesity as well as with resting metabolic rate [161].

PPARγ is a nuclear receptor, highly expressed in the WAT and BAT, but also in the muscle and the liver. It plays key roles in glucose homoeostasis and safe lipid storage through adipogenesis induction [6]. It is activated by endogenous ligands such as PUFAs (polyunsaturated fatty acids), such as eicosopentanoic acid, or the synthetic antidiabetic drug TZD (thiazolidinedione). TZD activates the browning of WAT. It was demonstrated that PRDM16 mediated this action [162]. A similar browning effect has not yet been described in human tissues. Therapeutic induction of PRDM16 protein expression could represent a strategy to enhance thermogenesis without unwanted side effects of TZD such as body weight gain [6].

Although studies on preadipocytes and mature brown adipocytes transplantation in rodents do not give conclusive results [163], subcutaneous transplant of embryonic BAT, as mentioned above, was shown to ameliorate the metabolic condition in obese [66] or diabetic mice [67]. Human pluripotent stem cells [164] and human BAT-derived stem cells [165] expanded in vitro can be differentiated into functional brown adipocytes. A brown adipocyte cell therapy could therefore be investigated as a way to restore functional BAT for the treatment of obesity and the metabolic syndrome.

CONCLUSION

In conclusion, supported by animal studies, new hopes have emerged in the treatment of obesity with BAT targeting. However, clinical trials have not yet given the expected results. Achieving BAT activation and subsequent increase in thermogenesis without any side effects (such as hunger, hyperthermia or cardiovascular consequences) through the identification of a selective human BAT activator remains an exciting challenge for the next few years. Highly selective and efficient β3AR agonists, β3AR sensitizers, TGR5 agonists or FGF21 replacement therapy are some of the methods under current development. However, to date, several issues need to be resolved before considering a potential therapeutic application for such a strategy. Functional BAT has not been identified in all human subjects tested, implying that the BAT-activating strategy may only be beneficial in a fraction of the population. Studies highlight an inverse correlation between body weight and functional BAT, but whether weight loss would restore BAT function has not been established. BAT targeting in humans increases thermogenesis and contributes to reducing fat mass; however, convincing evidence that it would also combat obesity and ameliorate insulin sensitivity and the metabolic profile remains to be found. Ultimately, reduction in cardiovascular risk and in complications of the metabolic syndrome would need to be achieved to provide full support for a BAT-activating therapeutic strategy.

FUNDING

N.L. is a postdoctoral Clinical Master Specialist and I.A.L. is a Senior Research Associate with the Belgian National Fund for Scientific Research (FRS-FNRS). Our present work is supported by grants from the D.G. Higher Education Scientific Research of the French Community of Belgium [grant number ARC 12/17-047] and the Fund for Scientific Medical Research (Belgium) [grant numbers CDR J.0100.15 and PDR T.1067.14].

Abbreviations

     
  • β3KO

    β3AR-knockout

  •  
  • ANP

    atrial natriuretic peptide

  •  
  • AR

    adrenergic receptor

  •  
  • BAT

    brown adipose tissue

  •  
  • BMI

    body mass index

  •  
  • BMP8B

    bone morphogenetic protein 8B

  •  
  • BNP

    brain natriuretic peptide

  •  
  • COX

    cyclo-oxygenase

  •  
  • CT

    computed tomography

  •  
  • DIO2

    type II iodothyronine deiodinase

  •  
  • FA

    fatty acid

  •  
  • FATP

    fatty acid transport protein

  •  
  • 18F-FDG

    2-[18F]fluoro-2-deoxy-D-glucose

  •  
  • FGF

    fibroblast growth factor

  •  
  • FNDC5

    fibronectin type III domain-containing 5

  •  
  • GLUT

    glucose transporter

  •  
  • HFD

    high-fat diet

  •  
  • IGF-1

    insulin-like growth factor 1

  •  
  • IL

    interleukin

  •  
  • NAFLD

    non-alcoholic fatty liver disease

  •  
  • NEFA

    non-esterified (‘free’) fatty acid

  •  
  • NPY

    neuropeptide Y

  •  
  • PET

    positron emission tomography

  •  
  • PGC1α

    PPARγ co-activator 1α

  •  
  • PGE2

    prostaglandin E2

  •  
  • PKA

    cAMP-dependent protein kinase

  •  
  • PPARγ

    peroxisome-proliferator-activated receptor γ

  •  
  • PRDM16

    PR domain-containing 16

  •  
  • SNS

    sympathetic nervous system

  •  
  • T3

    tri-iodothyronine

  •  
  • T4

    thyroxine

  •  
  • TAG

    triacylglycerol

  •  
  • TGR5

    G-protein-coupled bile acid receptor 1

  •  
  • TZD

    thiazolidinedione

  •  
  • UCP1

    uncoupling protein 1

  •  
  • WAT

    white adipose tissue

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