Hormonal signaling plays key roles in tissue and metabolic homeostasis. Accumulated evidence has revealed a great deal of insulin and estrogen signaling pathways and their interplays in the regulation of mitochondrial, cellular remodeling, and macronutrient metabolism. Insulin signaling regulates nutrient and mitochondrial metabolism by targeting the IRS-PI3K-Akt-FoxOs signaling cascade and PGC1α. Estrogen signaling fine-tunes protein turnover and mitochondrial metabolism through its receptors (ERα, ERβ, and GPER). Insulin and estrogen signaling converge on Sirt1, mTOR, and PI3K in the joint regulation of autophagy and mitochondrial metabolism. Dysregulated insulin and estrogen signaling lead to metabolic diseases. This article reviews the up-to-date evidence that depicts the pathways of insulin signaling and estrogen-ER signaling in the regulation of metabolism. In addition, we discuss the cross-talk between estrogen signaling and insulin signaling via Sirt1, mTOR, and PI3K, as well as new therapeutic options such as agonists of GLP1 receptor, GIP receptor, and β3-AR. Mapping the molecular pathways of insulin signaling, estrogen signaling, and their interplays advances our understanding of metabolism and discovery of new therapeutic options for metabolic disorders.

Since the definition of hormone by the British physiologist Ernest Starling in 1905 [1], hormone research has advanced in many areas, including new hormone discovery, functional characterization, biotechnology-assisted synthesis, and clinical application [2,3]. A hormone was defined as a molecule produced by the glands with internal secretion and delivered by the blood circulatory system to target tissues, regulating physiological functions [1]. Nowadays, it has been recognized that cytokines produced by non-gland cells or tissues (e.g., adipose tissue, liver, and skeletal muscle) function as hormones [3–5].

Insulin is secreted from pancreatic β-cells, which is critical for metabolic health and functions of various tissues such as muscle, adipose tissue, and liver [6–9]. Studies have established canonical insulin signaling pathways (e.g., IRS-PI3K-PDK1-Akt) and non-canonical insulin signaling pathways (e.g., IRS-PI3K-PDPK1-aPKCλ) in the regulation of glucose metabolism [7,10]. Moreover, insulin signaling modulates mitochondrial metabolism including mitochondrial biogenesis, dynamics, and autophagy (mitophagy, a mitochondrial quality control system that allows for the elimination of damaged and redundant mitochondria) [11], primarily through the Forkhead box O (FoxO) transcription factors [12]. Recent research has revealed the epigenetic role of insulin signaling via Snail and Slug in metabolic disorders [13–15].

Estrogen is mainly synthesized and secreted by the ovaries and placenta, which regulates the development of the reproductive system and nonreproductive tissue (e.g., adipose tissue, liver, muscle, and brain) function and homeostasis [16]. Estrogen signaling mediates metabolic homeostasis through its receptors (especially ERα and ERβ), which modulate mitochondrial homeostasis, autophagy, and epigenetic programming [3,5,17,18]. Dysregulation of estrogen signaling leads to metabolic disorders such as obesity, diabetes, cardiovascular diseases, liver diseases, muscle diseases, and neurodegenerative diseases [16,19–22].

Accumulated evidence has linked estrogen signaling to insulin signaling in metabolic regulation. For instance, both insulin and estrogen signaling cascades are involved in the regulation of mitochondria, autophagy, and protein degradation [12,23–25]. Sirt1 and PI3K serve as the mediators in the crosstalk of insulin and estrogen signaling, which plays essential roles in metabolism [26–28]. In this article, we present an updated view of the signaling pathways of insulin and estrogen, and how they interact in the regulation of metabolic homeostasis.

Insulin signaling

The canonical insulin signaling includes insulin receptor (IR)-mediated phosphorylation of IRSs proteins and activates phosphatidylinositol-3-kinase (PI3K) and downstream protein kinases, such as Akt (Figure 1A) [29]. During feeding status, Akt phosphorates FoxO1, retaining FoxO1 in the cytoplasm and suppressing hepatic gluconeogenesis. FoxO1 confers insulin sensitivity onto glucose-6-phosphatase expression) (Figure 1A) [10]. During fasting, IRS-PI3K-PDK1-Akt signaling was deactivated and leads to nuclear translocation of FoxO1, up-regulating gluconeogenic genes that encode phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatase, catalytic subunit (G6Pase), by coordinating with a complex of cAMP response element-binding protein (CREB) and transcription coactivator 2 (CRTC2), and CREB-binding protein (CBP) (Figure 1A) [10]. In addition, Akt phosphorylates mTORC1 to promote lipogenesis, protein synthesis, and gluconeogenesis [27,30–32] (Figure 1A). The non-canonical insulin signaling may bypass the canonical IRS-PI3K-PDK1-Akt cascade via PDPK1-aPKCλ branch [10,33]. In recent years, new mediators of insulin signaling have been discovered. For instance, insulin signaling may undergo transcriptional regulation by glucocorticoid receptor (GR) that binds to the IRS promotor (Figure 1A); interestingly, GR represses IRS1 but induces IRS2 expression [34]. At post-translational level, IRS could be glycosylated, O-GlcNAc modification of IRS contributes to insulin resistance, but how it interplays with IRS phosphorylation needs further exploration [35]. Akt as one of the key mediator of insulin signaling is under the regulation of lncRNAs, with ceRNA to activate Akt expression and other lncRNAs to down-regulate Akt (Figure 1A) [36,37].

Insulin signaling in metabolism

Figure 1
Insulin signaling in metabolism

(A) Insulin signaling mediates macronutrients metabolism. Following canonical IRS-PI3K-PDK1-Akt insulin signaling, feeding activates IRS phosphorylation at multiple tyrosine sites and activates PI3K and Akt (phosphorylation at Thr308), which phosphorates FoxO1 (Ser256), retains it in the cytoplasm, and suppresses the expression of gluconeogenic genes, phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatase (G6Pase), while fasting promotes gluconeogenesis. Upon feeding, activated Akt suppresses glycogen synthesis via phosphorylation of GSK3 (Ser9 and Ser21). Akt induces glycolysis via FoxO1 phosphorylation and activation of glucokinase gene expression. Akt stimulates protein synthesis via mTORC1 signaling pathway. Akt activates lipid synthesis via phosphorylation of TSC and FoxO1, which activates mTORC1 and SREBP1c and the lipogenic gene. Additionally, glucocorticoid receptor (GR) transcriptionally suppresses IRS1 and promotes IRS2 expression, and IRS1 (on Ser1101) and IRS2 (on Ser1149) could be posttranslationally modified by glycosylation (O-GlcNAc), but how it interferes with phosphorylation is not known. Akt could be mediated by lncRNA, either activation or suppression. (B) Insulin signaling regulates mitochondrial metabolism (mitochondrial biogenesis, fusion, and fission, mitophagy). Insulin signaling mediates mitochondrial biogenesis via FoxOs-mediated Tfam, NRF1, and PGC1α. FoxOs affect mitochondrial dynamics mainly through transcriptionally up-regulate the fusion proteins Mfn1/2 and down-regulate fission protein Drp1. Additionally, FoxOs post-transcriptionally suppress mitochondrial fission via promoting microRNA-484 (miR-484) expression and its binding with Fis1 mRNA and suppresses Fis1 translation. FoxOs promote mitophagy through transcriptional regulation of PINK1 and BNIP3.

Figure 1
Insulin signaling in metabolism

(A) Insulin signaling mediates macronutrients metabolism. Following canonical IRS-PI3K-PDK1-Akt insulin signaling, feeding activates IRS phosphorylation at multiple tyrosine sites and activates PI3K and Akt (phosphorylation at Thr308), which phosphorates FoxO1 (Ser256), retains it in the cytoplasm, and suppresses the expression of gluconeogenic genes, phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatase (G6Pase), while fasting promotes gluconeogenesis. Upon feeding, activated Akt suppresses glycogen synthesis via phosphorylation of GSK3 (Ser9 and Ser21). Akt induces glycolysis via FoxO1 phosphorylation and activation of glucokinase gene expression. Akt stimulates protein synthesis via mTORC1 signaling pathway. Akt activates lipid synthesis via phosphorylation of TSC and FoxO1, which activates mTORC1 and SREBP1c and the lipogenic gene. Additionally, glucocorticoid receptor (GR) transcriptionally suppresses IRS1 and promotes IRS2 expression, and IRS1 (on Ser1101) and IRS2 (on Ser1149) could be posttranslationally modified by glycosylation (O-GlcNAc), but how it interferes with phosphorylation is not known. Akt could be mediated by lncRNA, either activation or suppression. (B) Insulin signaling regulates mitochondrial metabolism (mitochondrial biogenesis, fusion, and fission, mitophagy). Insulin signaling mediates mitochondrial biogenesis via FoxOs-mediated Tfam, NRF1, and PGC1α. FoxOs affect mitochondrial dynamics mainly through transcriptionally up-regulate the fusion proteins Mfn1/2 and down-regulate fission protein Drp1. Additionally, FoxOs post-transcriptionally suppress mitochondrial fission via promoting microRNA-484 (miR-484) expression and its binding with Fis1 mRNA and suppresses Fis1 translation. FoxOs promote mitophagy through transcriptional regulation of PINK1 and BNIP3.

Close modal

Insulin in the regulation of macronutrient metabolism

The homeostasis of macronutrients, such as gluconeogenesis, glycolysis, protein synthesis and breakdown, lipogenesis, and lipolysis, is regulated by insulin. Insulin level and sensitivity are affected by the feeding and fasting cycle or diseased state, which affects the metabolism of these macronutrients as well as tissue-specific and systemic functions. As insulin sensitive tissues, liver, muscle, and adipose tissue respond to insulin signaling and affect their macronutrient metabolism during feeding-fasting cycle and pathological status. In the liver, the level of insulin increased upon feeding, which signals the liver to regulate hepatic glucose, protein, and lipid metabolism [38]. Following canonical IRS-PI3K-PDK1-Akt insulin signaling, feeding activates Akt, which phosphorates FoxO1, retains it in the cytoplasm and suppresses gluconeogenic genes, phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatase (G6Pase) expressions and hepatic gluconeogenesis (Figure 1A) [10,39]. On the other hand, fasting suppressed canonical IRS-PI3K-PDK1-Akt insulin signaling and deactivated Akt-reduced phosphorylation of FoxO1, which leads to nuclear translocation of FoxO1, and FoxO1 upregulates PEPCK and G6Pase, by coordinating with a complex of cAMP response element-binding protein (CREB) and transcription coactivator 2 (CRTC2), and CREB-binding protein (CBP) [10]. In addition, upon feeding mTORC2 phosphorylates Akt on Ser473 and activates Akt to control other metabolic activities in the liver, including glycogen production, glycolysis, and lipid synthesis (Figure 1A) [38]. Akt suppresses glycogen synthesis via phosphorylation of GSK3 and GSK3 independent pathway [40,41]. In addition, Akt induces glycolysis via FoxO1 phosphorylation and activation of glucokinase gene expression (Figure 1A) [42]. Through phosphorylating and inhibiting the TSC proteins, Akt stimulates the mTORC1 and protein synthesis pathways (Figure 1A) [27,31]. Akt activates lipid synthesis through phosphorylation of TSC and FoxO1, which activates mTORC1 and SREBP1c and the lipogenic gene program since SREBP1c is a transcription factor essential for the synthesis of fatty acids, triglycerides and cholesterol (Figure 1A) [43,44].

In the feeding state, insulin drives muscle growth and muscle mass maintenance. Insulin binds to the insulin receptor (IR) and activates the IRS-PI3K-Akt pathway, which inhibits the nuclear translocalization and transcriptional activity of FoxO1, FoxO3, and FoxO4. Proteasomal and autophagy–lysosomal protein breakdown is suppressed when FoxO1, FoxO3, and FoxO4 are inhibited [45]. Furthermore, amino acids and IRS-PI3K-Akt pathway stimulate the mammalian target of rapamycin complex 1 (mTORC1) to increase protein synthesis (Figure 1A), resulting in net protein gain and muscle growth [46–48]. While fasting or diabetes reduces insulin signaling, which increases FoxO isoform nuclear translocation and transcription of critical mediators of the ubiquitin–proteasome and autophagy–lysosome systems, resulting in a marked increase in protein degradation that outweighs protein synthesis, resulting in muscle atrophy and a high-protein-turnover state [46,49]. In addition, insulin activates the group I p21-activated kinase (PAK) isoforms PAK1 and PAK2, and PAK1/2 signaling was impaired by insulin resistance in skeletal muscle [50,51]. PAK1 is essential for insulin-stimulated GLUT4 translocation in mouse skeletal muscle. PAK2 is required for insulin-stimulated glucose uptake in glycolytic extensor digitorum longus muscle, but PAK1 is not required for whole-body glucose homeostasis and insulin-stimulated muscle glucose uptake [50]. Prolonged insulin exposure induced insulin resistance in primary human skeletal muscle-derived cells (HMDCs), as characterized by blunted IRS-1 phosphorylation (Tyr612) and Akt (Ser473) phosphorylation in response to an acute insulin stimulation. Prolonged insulin exposure suppressed glucose uptake, while increased compensatory expression of glucose transporter 1 (GLUT1) [52]. As insulin insensitive tissue, brain responds to insulin signaling and regulates cell plasticity and memory. Insulin signaling activates IRS1-PI3K-PDK1-Akt-AMPK and IRS1-PI3K-c-Raf-MEK signaling, and converges on ERK and memory through RSK/CREB/CBP-dependent gene transcription, which are essential for cell plasticity and memory in the hippocampus [53,54]. At the same time, insulin signaling axis affects mediators of glucose utilization (GLUT, GSK3), mitochondrial function (FoxO1), and energy metabolism (mTOR, AMPK) to support hippocampal integrity. Thus, insulin signaling affects macronutrients metabolism through targeting FoxOs and mTOR (Figure 1A).

Insulin in the regulation of mitochondria

Mitochondrion is an organelle that primes biochemical processes of respiration and energy production [55–57]. Its homeostasis is jointly maintained by mitochondrial biogenesis, mitochondrial dynamics (fusion or fission), and mitophagy (mitochondrial autophagy) [12,58]. Insulin signaling mediates mitochondrial function and disease status [56,57], which is fine-tuned through FoxOs and PGC1α (Figure 1B). FoxOs play key roles in the triad of mitochondrial biogenesis, dynamics, and mitophagy as a transcription factor in the canonical IRS-PI3K-Akt insulin signaling pathway [12]. FoxOs differentially regulate mitochondrial biogenesis via Tfam, NRF1, and PGC1α in different tissues (Figure 1B) [12,59,60]. FoxOs affect mitochondrial dynamics mainly through transcriptionally up-regulate the fusion proteins Mfn1/2 and down-regulate fission protein Drp1 (Figure 1B) [12,61]. Additionally, FoxOs posttranscriptionally suppress mitochondrial fission via promoting microRNA-484 (miR-484) expression and its binding with Fis1 mRNA and suppresses Fis1 translation (Figure 1B) [62]. In addition, fasting or insulin resistance promote FoxOs activity and its up-regulation on mitophagy (Figure 1B) [11]. Mechanistically, FoxOs promote mitophagy through transcriptional regulation of PINK1 [63,64] and BNIP3 (Figure 1B) [65,66].

Independent of FoxOs, insulin could mediate mitochondrial biogenesis through Akt-PGC1α and CREB- PGC1α signaling [67]. In response to insulin, activated Akt induces the phosphorylation of PGC1α by Cdc2-like kinase 2 (Clk2) and suppress mitochondrial biogenesis [68,69]. Furthermore, Akt phosphorylates CBP/P300 and suppresses the recruitment of the CREB transcription factor to induce PGC1α transcription [70,71]. Thus, insulin signaling regulates mitochondrial metabolism through targeting FoxOs-mediated mitochondrial biogenesis, dynamics and mitophagy as well as PGC1α-dependent, FoxOs-independent mitochondrial biogenesis.

Impaired insulin signaling and metabolic diseases

Aberrant insulin signaling is most prominent in diabetes and associated metabolic diseases (e.g., diabetes and obesity). Diabetes is characterized by hyperglycemia, which is defined as a fasting blood sugar level more than 126 mg/dL [72]. Type 1 and type 2 diabetes are the two main types of the disease, which affects more than 537 million adults worldwide in 2021 [73]. Type 1 diabetes mellitus (T1DM) is an autoimmune disease in which the immune system destroys insulin-producing β cells [74]. Type 2 diabetes mellitus (T2DM) is characterized by high insulin concentrations, at least at its early stages due to insulin resistance, which contrasted the lack of insulin in T1DM [75]. Both diabetic conditions will lead to dysfunctional insulin signaling, such as IRS→PI3K→FoxO1, which would lead to metabolic dysfunctions and affect protein catabolism, lipolysis and the formation of ketone bodies [76], and cause metabolic syndrome [77,78].

Obesity and diabetes are significantly associated with the development of nonalcoholic fatty liver disease (NAFLD), especially when the patients are treated with insulin [79–81]. Clinical cross-sectional study of patients with Type 2 diabetes mellitus indicated that lower fasting and postprandial glucagon-to-insulin ratio was significantly associated with the presence of NAFLD [82]. The production of glucose and triglycerides is elevated in Type 2 diabetes and nonalcoholic fatty liver disease (NAFLD), which was supported by the selective hepatic insulin resistance theory, in which insulin drives de novo lipogenesis (DNL) without suppressing glucose production [83,84], In overweight human, overfeeding saturated fat increased the greatest level of increased intrahepatic triglyceride (IHTG), insulin resistance, and harmful ceramide [85], And overfeeding sugar increased de novo lipogenesis, while overfeeding saturated fat increased lipolysis and unsaturated fat decreased lipolysis [85]. While weight loss reduced intrahepatic triglyceride IHTG content via lowering hepatic DNL, at least in part [84]. While a clinical study on obese subjects with or without NAFLD found that NAFLD individuals attenuated, not increased, glucose-stimulated/high-insulin lipogenesis [86]. Thus, early detection and treatment of aberrant insulin signaling are critical for prevention and treatment of liver disease.

High fat diet induced obesity leads to impaired insulin access to skeletal muscle and glucose uptake, while polyunsaturated fat-rich diets improve insulin sensitivity and lower the risk of Type 2 diabetes. In comparison with a saturated high fat diet, a polyunsaturated high fat diet sustained insulin sensitivity and insulin availability to muscle [87]. In addition, recent study indicates the pathological role of myokines generated by diseased striated muscle, such as myokine/cardiokine MG53, might increase systemic insulin resistance [88,89]. Thus, it would be critical for mitigating aberrant insulin signaling induced muscle dysfunction. Correction of poor glycemic control and use of insulin leads to increased skeletal muscle mass in Japanese patients with Type 2 diabetes [90,91]. Insulin therapy for Type 2 diabetes enhanced skeletal muscle index (SMI) and protected against Sarcopenia, a loss of skeletal muscle mass and strength that occurs with age and is a primary cause of disability and mobility limits [91]. Interestingly, short-term immobilization boosts intramyocellular diacylglycerol and decreases insulin sensitivity in muscle through increased lipin1 activity [92]. Therefore, insulin plus physical activity therapy would provide promising strategies for diabetic muscle disease.

Unlike insulin-sensitive tissues (e.g., the liver, muscle, and adipose tissue), insulin does not increase glucose uptake/metabolism in the brain [93]. However, insulin regulates brain functions and neurodegenerative diseases across different regions and cross-talk with other tissues, such as liver, to fine-tune whole body function [93]. For example, insulin modulates cerebral bioenergetics, boosts synaptic survival, and dendritic spine formation and raises the turnover of neurotransmitters like dopamine, according to new findings from human and animal studies. Insulin also affects proteostasis, impacting amyloid peptide clearance and tau phosphorylation [94–97], both of which are hallmarks of Alzheimer’s disease. Insulin affects vasoreactivity, lipid metabolism, and inflammation, all of which affect vascular function. Insulin dysregulation may contribute to neurodegeneration via these numerous routes [98]. Insulin signaling has been found to be desensitized in the brains of patients, drugs that can resensitize insulin signaling have been tested to evaluate if this strategy can alter disease progression [54]. Insulin administration has shown good effects in preclinical studies [99,100]. In a 12-month double-blind clinical research of patients with amnestic moderate cognitive impairment or Alzheimer’s disease, intranasal insulin therapy had no cognitive or functional advantages in the primary intention-to-treat group [101], the limitations would be the feasibility challenge with insulin administration device and it has never been used in patients with Alzheimer’s disease before. Altogether insulin plays important roles in maintaining the physiological homeostasis in different tissues and derangement of insulin signaling contributes to diabetes, obesity, muscle diseases, liver diseases, and neurodegenerative diseases via targeting specific tissue and cross-talk among different tissues.

New therapeutic options

Insulin and insulin analogues have been widely used for therapeutic options over the years [102]. However, the reported side effects and therapeutic inefficacy promote the development of new therapeutic alternatives, such as glucagon-like peptide-1 (GLP1) receptor agonists and glucose-dependent insulinotropic polypeptide (GIP) receptor agonists, to restore insulin secretion for the treatment of T2DM [103]. In 2017, a dual GLP1/GIP receptor agonist, NNC0090-2746, was developed and showed significant improvement of glycemic control and reduction of body weight in clinical trial [104]. Since then, similar drugs have been developed, and the Food and Drug Administration has approved Mounjaro (tirzepatide, a single molecule) that selectively binds to the receptors for both GIP and GLP-1 to treat T2DM [105]. However, there are acute side effects such as, qualmishness, loose stools, food aversion, and bloating abdomen.

Obesity is associated with insulin resistance. β3-adrenergic receptor (β3-AR), mainly located in urinary bladder, brown and white adipose tissues, has been shown to play an important role in activation of brown adipose tissue thermogenesis, white adipose tissue lipolysis, and insulin sensitivity [106,107]. Mirabegron, a β3-AR agonist that is only approved for the management of overactive bladder, activates thermogenesis of brown adipose tissue, lipolysis of white adipose tissue and insulin sensitivity in preclinical studies [108]. However, the experimental subjects are healthy women with normal BMI; further clinical trials on patients with metabolic diseases (i.e., diabetes and obesity) are warranted to confirm the efficacy of β3-AR agonist on the treatment of these diseases.

NAFLD is associated with obesity and is directly intertwined with insulin resistance and T2DM [109]. In varying degrees, experimental agents that target aspects of liver intermediary metabolism (such as ketohexokinase inhibitor, diacylglycerol acyltransferase inhibitor, PPARα-PPARδ agonist) have also proven beneficial, but their use may be limited by adverse effects [109]. Therefore, testing the approved and candidate drugs for diabetes and obesity in NAFLD patients would be promising.

Although new therapeutics for ameliorating insulin deficiency and insulin resistance have been developed for T2DM, most of the promising candidates were studied in experimental models and preclinical trials. For their final approval as clinical treatments, however, rigorous clinical trials with specific patients are required, especially factors such as age range, gender and ethnicity should be considered. In particular, biological sex plays a significant role in the development of metabolic diseases associated with insulin dysfunction, such as diabetes [110,111], cardiovascular diseases [112,113], and NAFLD [114–116]. The sexual hormone, estrogen, accounts in part for the fact that females are less susceptible than males. Estrogen therapy has been shown to improve cardiovascular health and insulin sensitivity [28,117,118], potentiating the critical role of estrogen in preserving metabolic health and insulin function. In the following section, we review the role of estrogen signaling in metabolic health and disease.

Estrogen and its receptors

Estrogen is a sex hormone that is involved in the development and regulation of the female reproductive system as well as secondary sex characteristics [119,120]. Estrone (E1), estradiol (E2), and estriol (E3) are the three primary endogenous estrogens with estrogenic hormonal activity, among which E2 is the most powerful and common one. The current review will focus on E2. Aromatase is the enzyme catalyzes the conversion of steroids to estrogens [17]. Estrogen is largely generated in the ovary in premenopausal women, while adipose tissue is the primary site for peripheral estrogen synthesis and metabolism [121,122]. Estrogen acts by binding to specific receptors, designated estrogen receptors (ERs), which activate transcriptional processes and/or signaling events that govern gene expression. There are three types of estrogen receptors, ERα, ERβ, and GPER (Figure 2A) [123,124]. Emerging evidence has indicated the critical functions of estrogen in maintaining metabolic health of extragonadal tissues, dysfunctional estrogen signaling has contributed to metabolic diseases, such as obesity, diabetes, cardiovascular disease, and liver disease [19,112,115,123,124].

Estrogen signaling in metabolism and metabolic diseases

Figure 2
Estrogen signaling in metabolism and metabolic diseases

Estrogen-ERα mediates mitochondrial metabolism through its receptors ERα and GPER. ERα increases cellular mitochondrial DNA content via nuclear receptor subfamily 4 group A member 1 (Nr4a1) activation. ERα mediates protein kinase A (PKA) dependent mitochondrial dynamic and mitophagy. In addition, ERα mediates mitochondrial fission by dynamin-related protein 1 (Drp1) and uncoupled respiration thermogenesis by uncoupled protein 1 (Ucp1), which is dependent on the transcriptional regulation of ERα on mtDNA polymerase γ subunit Polg1. GPER affects mitochondrial biogenesis through its activation of cAMP-PKA-CREB pathway.

Figure 2
Estrogen signaling in metabolism and metabolic diseases

Estrogen-ERα mediates mitochondrial metabolism through its receptors ERα and GPER. ERα increases cellular mitochondrial DNA content via nuclear receptor subfamily 4 group A member 1 (Nr4a1) activation. ERα mediates protein kinase A (PKA) dependent mitochondrial dynamic and mitophagy. In addition, ERα mediates mitochondrial fission by dynamin-related protein 1 (Drp1) and uncoupled respiration thermogenesis by uncoupled protein 1 (Ucp1), which is dependent on the transcriptional regulation of ERα on mtDNA polymerase γ subunit Polg1. GPER affects mitochondrial biogenesis through its activation of cAMP-PKA-CREB pathway.

Close modal

The traditional process involves the cytosolic ERα being activated by the ligand (17b-estradiol, E2) coupled to heat shock protein 90 (Hsp90), dimerization of ERα, and direct DNA binding to estrogen response elements (ERE), or interaction with other transcription factors, such as the binding with AP1/SP1 sites [125]. Through ERα post-translational changes such as palmitoylation on active cystines and direct contact with caveolin-1, a tiny pool of ERα located near to the plasma membrane mediates the membrane-initiated signal (MISS) pathway. Membrane ERα interacts with protein kinases (Src and PI3K) or G-coupled protein ai (Gai) in response to E2 activation, activating endothelial NO synthase and several signaling cascades (Akt, PKA, and ERK1/2) (eNOS) [125]. Thus, estrogen signaling plays distinctive roles in metabolic diseases through different localization of ERs and may arise different signaling pathways.

Estrogen-ER signaling in protein homeostasis

Estrogen signaling has been reported to affect protein stability and degradation, maintaining metabolic homeostasis, such as muscle strength and neuronal health [126–129]. Estrogens affect female skeletal muscle strength through mediating key proteins, protein synthesis and degradation, satellite cell function, apoptosis, and inflammation [126,127]. It has also shown that estrogen is essential for muscle recovery in female mice with Duchenne muscular dystrophy (DMD) [130]. Estrogens influence female skeletal muscle strength by preserving muscle mass and the quality of contractile proteins, such as myosin heavy chain and actin proteins [131,132]. Estrogens influence myosin heavy chain binding to actin to generate force via phosphorylation of the regulatory light chain. Protein turnover, proteolysis, and apoptosis are some of the processes influenced by estrogens that affect muscle mass [133–135]. Inflammation and satellite cell function are also estrogen sensitive and can contribute to muscle strength preservation [134,135]. Estrogen plays a crucial role in the processing of amyloid precursor protein (APP) and general neuronal health, which is partially via the modulation of brain-derived neurotrophic factor (BDNF), a factor that is similarly decreased in postmenopausal women and negatively associated with AD progression [128,129].

However, the direct target of estrogen has yet to be discovered. Although studies have implicated ERα in autophagic degradation pathway [136], the direct link between ERα, autophagy and these target degraded proteins should be elucidated.

Estrogen-ER signaling in mitochondrial regulation

Estrogens affect mitochondrial functions, including their biogenesis, dynamics, and turnover through ERs. For instance, cardiomyocyte mitochondrial and plasma membrane localized ERα, not ERβ, controls mitochondrial structure and function [137]. However, ERβ has been found to be localized in cancer cells' mitochondria, where it appears to influence the action of mitochondrial DNA or mitochondrial transcription factors [138]. Constant ERα overexpression increases cellular ATP content as well as mitochondrial DNA content in differentiated myoblastic C2C12 cells via nuclear receptor subfamily 4 group A member 1 (Nr4a1) activation (Figure 2A); however, the direct regulation of ERα on Nr4a1 at the transcriptional level requires further investigation [139]. It has been shown that palmitic acid treatment in cells or high fat diet intervention in animals impaired hepatic mitochondrial function, inducing oxidative stress and activation of c-Jun N-terminal kinase (JNK) which has been related to the development of insulin resistance and steatosis [140]. E2 treatment induced mitochondrial biogenesis in line with decreased oxidative stress and suppression of sustained JNK activation [141].

ERα mediates mitochondrial dynamics and mitophagy, maintaining metabolic homeostasis and insulin sensitivity [23,142]. ERα in the muscle has been shown to be essential for systemic insulin sensitivity and lipid decomposition. Muscle specific ERα knockout impaired glucose homeostasis and increased adiposity via mediating protein kinase A (PKA) dependent mitochondrial dynamic and mitophagy (Figure 2A) [24]. Moreover, loss of ERα also confers to compromised mtDNA turnover by a balanced decrease in mtDNA replication and degradation [24]. In addition to ERα, GPER could also activate cAMP-PKA and mitochondrial function [143]. In 3T3L1 adipocytes, treatment of GPER agonist induces mitochondrial biogenesis, which was abrogated by PKA inhibitor, indicating the function of E2-GPER-PKA in mitochondrial biogenesis (Figure 2A) [143]. However, a recent study indicated that after postnatal development is complete, ERα function is no longer required to protect against HFD-induced skeletal muscle metabolic derangements. This may due to the duration of HFD treatment or mouse models [144]. In white adipose tissue, ERα controlled oxidative metabolism by restraining mitophagy. In brown adipose tissue, ERα mediates mitochondrial fission by dynamin-related protein 1 (Drp1) and uncoupled respiration thermogenesis by uncoupled protein 1 (Ucp1), which is dependent on the transcriptional regulation of ERα on mtDNA polymerase γ subunit Polg1 (Figure 2A) [142]. The direct target of estrogen signaling and ERs in mitochondrial homeostasis is still under investigation.

Impaired estrogen signaling and metabolic diseases

Biological sex plays a significant role in the development of metabolic diseases, such as diabetes [110,111], cardiovascular diseases [112,113], and NAFLD [114–116], with females experiencing more protection than males. For example, women have more body fat than males; however, the pear-shaped body fat distribution of many women is associated with decreased cardiometabolic risk, in contrast with the detrimental metabolic effects of apple-shaped obesity characteristic of men [145]. As it tends to diminish with the onset of menopause. For example, early menopause (before 40 years of age) or low levels of estrogens (also known as hypoestrogenaemia) in young women (18–40 years) both accelerated the morbidity of atherosclerosis [146,147], a 2.6-fold increase in CVD risk, and an increased risk of CVD-related mortality [148,149]. However, the loss of estrogen may be restored with hormone replacement treatment, this defense appears to be fueled by female sex hormones (estrogens) [18,111].

The critical roles of ERs among both genders in metabolic diseases have been underlined in both human and animal models. Clinical study indicated that the polymorphism of ERβ gene reduced the risk of developing T2D [150]. In physically active adults, polymorphism of ESR1 rs2234693 allele, not the T allele, protects against muscle injury by lowering muscle stiffness [151]. A systemic meta-analysis indicated the protective role of estrogen treatment on Alzheimer’s disease (AD) and Parkinson’s disease (PD) [152]. A clinical study indicated the beneficial role of estrogen on nigrostriatal dopaminergic neuron degeneration in PD [153]. Many of the functional implications for ERs in modulating cardiometabolic risk have been discovered in rodents, where female mice with ESR1 mutations develop age-dependent vascular dysfunction and metabolic syndrome traits such as obesity, glucose intolerance, and insulin resistance [154,155]. All the evidence underpins the critical role of ERs in maintaining metabolic homeostasis and potentiating derangement of estrogen signaling contributes to metabolic diseases.

Estrogen deficiency or loss of ERs has been collectively leads to metabolic syndrome. Both genetic and pharmacological manipulation of ERα and ERβ demonstrated the critical role of estrogen and receptors in maintaining metabolic diseases [125,156–158]. Global knockout ERα in mice recapitulate the phenotype of humans with rare inactivating receptor mutations and genetic polymorphisms in the receptor, which is exhibited by adiposity, reductions in energy expenditure and increased food intake, but they also exhibit glucose intolerance, insulin resistance, and reduced endothelial-derived nitric oxide production (vasculoprotective molecule), thus demonstrating the critical role for ESR1 in regulating energy, metabolic, and vascular homeostasis [155,159,160]. Estrogen deficiency in mice delayed myoregeneration in injured muscles and estrogen administration under ovariectomized conditions rescued delayed myoregeneration, suggesting that estrogen is an essential factor in the myoregeneration process via its receptor ERα and ERβ [161]. Specific muscle loss of ERα impaired muscle contractile function, implying that the beneficial effects of estradiol on muscle strength are dependent on ERα [162]. It has been revealed that ERα plays distinguishable role in sex-specific manner in liver diseases; however, Erα is essential for maintaining metabolic health in both genders [163,164]. For example, hepatic ERα plays a significant role in the sex-specific response to a HFD treatment and has different effects on the health of the liver in males and females as females are more susceptive to control the detrimental effects of a HFD than males, such as promoting mitochondrial fatty acid oxidation [164]. Despite less ERα protein expression in metabolically active tissues than female mice, male mice nonetheless need ERα for proper immunometabolic function, and ERα signaling is required for exercise-induced protection of hepatic steatosis as loss of ERα abolished the beneficial effects of physical exercise on immunometabolic function [163].

Given the critical role of estrogen and gender difference in metabolic disease, clinical trials should be designed to test drug efficacy and safety according to sex, age, and reproductive stage (i.e., menopause) as lack of adequate knowledge of gender difference and response in metabolic diseases [165,166]. For example, younger females are more susceptible to develop metabolic diseases than males due to difference in insulin sensitivity and glucose disposal ability (especially diabetes and its comorbidities) [167,168], while this tendency switches after the age of 40, potentiating the critical role of sexual hormones in controlling insulin signaling [169]. It may be due to the expression and active profile of ERs upon exercise in metabolically active tissues, such as muscle [170,171]. Therefore, understanding the molecular mechanism about how estrogen and ERs in maintaining metabolic homeostasis is critical for testing or designing new therapeutics for treating estrogen related metabolic diseases.

Energy sensors Sirt1 and mTOR-mediated cross-talk

Insulin signaling controls nutrients metabolism and mitochondrial metabolism through targeting FoxOs and PGC1α (Figure 1A,B). Estrogen signaling fine-tunes protein turnover and mitochondrial metabolism primarily through its receptors, especially ERα (Figure 2A). Recently, Sirt1 has been found to interact with ERα, which converges insulin signaling and estrogen signaling. The interaction of ERα with Sirt1 is evident in the combination of deacetylation of ERα by Sirt1 and ERα transcriptional regulation of Sirt1 expression (Figure 3A) [26,27,172]. As a transcription factor, ERα binds to the promoter of Sirt1 and increases Sirt1 expression in breast cancer cell line [26]. We have for the first time revealed the cross-talk of ERα and Sirt1 in adipose tissue [27,173]. Our research reveals that a more active estradiol-ER signaling, which dials down autophagy and adipogenesis, is the cause of the lower visceral adiposity in females (compared with males) [136]. Furthermore, Sirt1 could function as downstream of ERα and also deacetylates ERα to inhibit mTOR-ULK1 dependent autophagy and adiposity [27,173]. This result revealed a new mechanism of Sirt1 regulating autophagy in adipocytes and shed light on sex difference in adiposity [27]. It has recently been discovered that E2 exerts its metabolic benefits by directly recruiting the ERα-Mc4r gene, which induces melanocortin-4 receptor (MC4R) signaling in the neurons of the ventromedial ventromedial hypothalamic nucleus (VMHvl) [174]. The regulatory fashion of ERs on other target genes like Sirt1 and Mc4r warrants further investigation.

The cross-talk of insulin signaling with estrogen signaling

Figure 3
The cross-talk of insulin signaling with estrogen signaling

(A) The convergence of insulin signaling and estrogen signaling via energy sensor Sirt1 or mTOR. ERα increases the level of Sirt1, which deacetylates IRS2 (multiple lysine sites) and regulates IRS1 phosphorylation, and it regulates downstream PI3K-Akt-FoxOs signaling. ERα interacts with FoxOs through the phosphorylation of mTORC2 on Akt (Ser473) and Akt (Thr308) on FoxOs, at the same time, FoxOs transcriptionally regulate Sestrins, which regulates mTOR signaling. (B) Estrogen- ERα cascade activates PI3K-Akt-FoxO1 independent of IRS-mediated insulin signaling and suppresses gluconeogenesis. Estrogen signaling activates FoxO3, which might be due to the compensatory role of FoxO3 for FoxO1 deactivation.

Figure 3
The cross-talk of insulin signaling with estrogen signaling

(A) The convergence of insulin signaling and estrogen signaling via energy sensor Sirt1 or mTOR. ERα increases the level of Sirt1, which deacetylates IRS2 (multiple lysine sites) and regulates IRS1 phosphorylation, and it regulates downstream PI3K-Akt-FoxOs signaling. ERα interacts with FoxOs through the phosphorylation of mTORC2 on Akt (Ser473) and Akt (Thr308) on FoxOs, at the same time, FoxOs transcriptionally regulate Sestrins, which regulates mTOR signaling. (B) Estrogen- ERα cascade activates PI3K-Akt-FoxO1 independent of IRS-mediated insulin signaling and suppresses gluconeogenesis. Estrogen signaling activates FoxO3, which might be due to the compensatory role of FoxO3 for FoxO1 deactivation.

Close modal

Sirt1 could physically interacts with IRS2 and the deacetylase activity of Sirt1 is required for the deacetylation and tyrosine phosphorylation of IRS-2 upon insulin treatment, which is critical for the canonical insulin signaling (Figure 3A) [175,176]. In addition, Sirt1 promotes the expression of Rictor, a component of mTORC2, which phosphorylates Akt at Ser473, loss of Sirt1 in the liver confers to decreased expression of Rictor and decreased phosphorylation of Akt and constant activation of FoxO1 [177], which is opposite of the finding that liver specific loss of FoxO1 impairs fasting- and cAMP-induced glycogenolysis and gluconeogenesis [178]. Thus, how Sirt1 affects mTOR-Akt cascade should be further confirmed in different tissues and various physiological condition. Recently, we found that Sirt1 directly deacetylates Akt and increases its phosphorylation in adipocytes and mediates adipocyte autophagy and adiposity [27,179]. It provides evidence about how Sirt1 affects insulin signaling by direct targeting Akt in adipocytes. But how Sirt1 mediates insulin signaling in different cells and tissues under physiological and pathological conditions should be further explored. mTORC2 could phosphorylates Akt and activated Akt phosphorylates FoxOs and regulates downstream pathways. In addition, FoxOs could cross-talk with mTOR signaling through Sestrins (Figure 3A). Mechanistically, FoxO1 binds to the promoter of Sestrin3 and induces Sestrin3 expression, but not Sestrin1 and Sestrin2 [180,181], and Sestrin3 inhibits mTORC1 signaling in a TSC2-dependent manner. Although FoxOs and Sestrins have been extensively studied for their involvement in metabolic diseases [182–184]; however, how FoxOs-Sestrin-mTOR cascade participates in metabolic regulation and diseases is still largely unknown. It would be interesting to investigate this cascade affects cellular metabolism under different nutritional, hormonal, and pathological status.

PI3K-mediated cross-talk

Estrogen–ER signaling has been found to maintain insulin sensitivity, potentiating the cross-talk of estrogen signaling and insulin signaling [28,185,186]. In male and ovariectomized (OVX) female mice, FoxO1 was found to be required for the improvement of estrogen on insulin resistance, which is through activation of ERα- PI3K-Akt-FoxO1 signaling, which is independent of IRS1 and IRS2 (Figure 3B) [28]. Moreover, subcutaneous 17β-estradiol (E2) implanting increased insulin sensitivity and decreased gluconeogenesis in male and ovariectomized (OVX) female control mice but not in liver-specific FoxO1 knockout (L-F1KO) animals. Activating the estrogen receptor ERα-PI3K-Akt-FoxO1 cascade, which is independent of classical insulin signaling involving IRS1 and IRS2, enables E2 to fine-tune glucose mentalism (Figure 3B) [28].

A similar study was shown in ovariectomized rats, subcutaneously administration of 17β-estradiol (E2) significantly improved insulin sensitivity in line with increased phosphorylation of Akt and its substrate Akt substrate of 160 kDa (AS160) Thr64, which was reported to regulate the plasma membrane-trafficking of GLUT4 [187,188]. However, a clinical study indicated the activation of FoxO3 by estrogen, acute E2 treatment potentiated the time-dependent effects of E2 on insulin by activating FoxO3, which is characterized by its dephosphorylation, and suppressing muscle atrophy in line with decreased MuRF1 protein level in early postmenopausal, but not late postmenopausal [189]. It might be due to the compensatory role of FoxO3 for FoxO1 deactivation. In addition, GSK3, as another substrate of PI3K-Akt, has been elucidated in ERα-Akt-GSK3 signaling pathway, in which estrogen prevents Tau phosphorylation, acting as a neuroprotective agent against the neurodegeneration of the female brain [190]. In addition, E2-induced and ERα-mediated glucose transporter 4 (GLUT4) translocation to plasma membrane is essential for glucose uptake [191,192], which also interacts with insulin signaling.

Furthermore, estrogen signaling may regulate insulin secretion by affecting pancreatic β cells. Treatment with estrogen restored insulin release from pancreatic β cells in mice genetically predisposed to protein misfolding due to insulin dysfunction, which is fine-tuned by activation of the endoplasmic-reticulum-associated protein degradation system [193,194]. Further studies are warranted to elucidate how estrogen medicates essential signaling pathways for preserving and restoring pancreatic insulin secretion. Estrogen signaling also affects other hormonal signaling pathways (e.g., FGF21). It has been shown that E2- β-cat/TCF-FGF21 signaling is essential for liver lipid metabolism and health; however, how ERα/ERβ are involved in β-cat/TCF binding to Fgf21 promoter and FGF21 is still not known, which warrants further investigation [25].

Females at the age of premenopause show lower risk of metabolic diseases than age-matched males, which is mainly due to the physiological secretion and function of estrogen (Figure 4). However, after menopause, the sex difference is normalized due to reduced secretion of estrogen in females. Recent studies indicate that administration of estrogen improves insulin sensitivity and glucose tolerance in both male and OVX female mice [28], while this improvement is absent in liver-specific FoxO1 knockout (L-F1KO) mice, demonstrating the critical role of estrogen-FoxO1 axis in the protective effects. In both male and OVX females, heart specific IRS1/2 double knockout induces cardiac insulin resistance and diabetic cardiomyopathy [117]. Administration of estrogen improves the cardiac conditions and insulin sensitivity in both males and OVX females, suggesting that IRS1/2 is dispensable for the effects of estrogen, in line with activation of Akt and FoxO1 by estrogen [117]. Together, estrogen plays a critical role in the sex difference of metabolic diseases (Figure 4), in part by targeting on PI3K and the downstream Akt-FoxO1 signaling.

Sex difference in metabolic diseases and the role of estrogen in this sex-dependent regulation

Figure 4
Sex difference in metabolic diseases and the role of estrogen in this sex-dependent regulation

(A) In premenopausal conditions, females show lower risk of metabolic diseases and higher estrogen levels than males, mainly due to the activated PI3K-Akt pathway. The females exhibit metabolic health, insulin sensitivity, and glucose tolerance. However, the difference is normalized by menopausal transition, hallmarked by decreased estrogen secretion in females. (B) Ovariectomized (OVX) females exhibit metabolic diseases (such as diabetes, cardiovascular disease, and fatty liver disease), insulin resistance, and glucose intolerance. Administration of estrogen in males and OVX females improves metabolic health, insulin sensitivity and glucose tolerance, normalizing the sex difference. The potential target of estrogen is the activation of PI3K/Akt signaling.

Figure 4
Sex difference in metabolic diseases and the role of estrogen in this sex-dependent regulation

(A) In premenopausal conditions, females show lower risk of metabolic diseases and higher estrogen levels than males, mainly due to the activated PI3K-Akt pathway. The females exhibit metabolic health, insulin sensitivity, and glucose tolerance. However, the difference is normalized by menopausal transition, hallmarked by decreased estrogen secretion in females. (B) Ovariectomized (OVX) females exhibit metabolic diseases (such as diabetes, cardiovascular disease, and fatty liver disease), insulin resistance, and glucose intolerance. Administration of estrogen in males and OVX females improves metabolic health, insulin sensitivity and glucose tolerance, normalizing the sex difference. The potential target of estrogen is the activation of PI3K/Akt signaling.

Close modal

Accumulated evidence depicts a great deal of insulin signaling and estrogen signaling in metabolic regulation. Dysregulation of insulin and estrogen signaling causes metabolic diseases, such as obesity, diabetes, cardiovascular diseases, muscle diseases, liver diseases, and neurodegenerative diseases. Although distinctive in pathways, insulin signaling and estrogen signaling may regulate macronutrients metabolism, mitochondrial homeostasis (mitochondrial biogenesis, dynamics and mitophagy) and other hormones. Insulin signaling affects macronutrients metabolism and mitochondrial metabolism mainly through IRS-PI3K-Akt regulation of FoxOs and PGC1α. Estrogen signaling fine-tunes protein turnover and mitochondrial metabolism through its receptors (ERα, ERβ and GPER), especially ERα. In addition, insulin signaling may interact with estrogen signaling via Sirt1, mTOR and PI3K. E2-ERα transcriptionally promotes Sirt1 expression and in turn Sirt1 could deacetylate ERα, which mediates mTOR signaling and autophagy. Sirt1 deacetylates FoxOs, which is the key transcription factor in insulin signaling. FoxOs interplays with mTOR signaling, in which FoxOs transcriptionally regulate Sestrins and Sestrins-mTOR signaling node. However, how FoxOs-Sestrins-mTOR cascade participates in the cellular metabolism and metabolic diseases remains largely unknown. On the other hand, insulin signaling interplays with estrogen signaling through PI3K. But how E2-ERα activates PI3K-Akt-FoxOs needs more investigations. Future studies are warranted to further elucidate the function of insulin signaling and estrogen signaling, especially their cross-talk in specific tissues and at global level, for the purpose of preventing dysfunctional hormone-related metabolic diseases and designing new therapeutic strategies.

NA

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

The Figures were created with BioRender. This work was supported in part by the American Heart Association [grant number 18TPA34230082 (to Z.C.)] and the USDA National Institute of Food and Agriculture [grant number 1020373 (to Z.C.)].

Open access for this article was enabled by the participation of University of Florida in an all-inclusive Read & Publish agreement with Portland Press and the Biochemical Society under a transformative agreement with Individual.

Zhipeng Tao: Conceptualization, Resources, Writing—original draft. Zhiyong Cheng: Conceptualization, Supervision, Funding acquisition, Writing—review & editing.

β3-AR

β3-adrenergic receptor

AD

Alzheimer’s disease

Akt

Protein kinase B

AMPK

AMP-activated protein kinase

aPKCλ

atypical protein kinase C λ

APP

amyloid precursor protein

AS160

Akt substrate of 160 kDa

BDNF

brain-derived neurotrophic factor

c-Raf

RAF proto-oncogene serine/threonine-protein kinase

CBP

CREB-binding protein

CeRNA

Competing endogenous RNA

Clk2

Cdc2-like kinase 2

CREB

cAMP response element-binding protein

CRTC2

transcription coactivator 2

CVD

cardiovascular disease

DMD

Duchenne muscular dystrophy

Drp1

Dynamin-related protein 1

E2

estradiol

ERα

estrogen receptor α

ERβ

estrogen receptor β

FGF21

fibroblast growth factor 21

Fgf21

fibroblast growth factor 21 gene

FoxO1

Forkhead Box O1

FoxO3

Forkhead Box O3

FoxO4

Forkhead Box O4

G6Pase

glucose-6-phosphatase

Gai

G-coupled protein ai

GIP

glucose-dependent insulinotropic polypeptide

GLP1

glucagon-like peptide-1

GLUT1

glucose transporter 1

GLUT4

glucose transporter 4

GPER

G-protein-coupled estrogen receptor 1

GSIS

glucose-stimulated insulin secretion

GSK3

glycogen synthase kinase-3

HFD

high fat diet

Hsp90

Heat shock protein 90

IHTG

intrahepatic triglyceride

IR

insulin receptor

IRS1

insulin receptor substrate-1

IRS2

insulin receptor substrate-2

JNK

c-Jun N-terminal kinase

LncRNA

long non-coding RNA

LTKOIRS

liver-specific Irs1, Irs2 and FoxO1 triple knockout

MC4R

Melanocortin-4 receptor

MEK

mitogen-activated protein kinase

miR-484

microRNA-484

mTORC1

mammalian target of rapamycin complex 1

mTORC2

mammalian target of rapamycin complex 1

NAFLD

nonalcoholic fatty liver disease

NRF1

nuclear Respiratory Factor 1

OVX

ovariectomized

PAK

p21 (RAC1) activated kinase

PAK1

p21 (RAC1) activated kinase 1

PAK1/2

p21 (RAC1) activated kinase 1/2

PAK2

p21 (RAC1) activated kinase 2

PD

Parkinson’s disease

PDPK1

phosphoinositide-dependent kinase 1

PEPCK

phosphoenolpyruvate carboxykinase

PGC-1α

peroxisome proliferator-activated receptor γ coactivator 1-α

PI3K

phosphoinositide 3-kinase

SAT

subcutaneous adipose tissue

SIRT1

Sirtuin 1

STZ

streptozotocin

T1DM

Type 1 diabetes mellitus

T2DM

Type 2 diabetes mellitus

Tfam

transcription Factor A

Ucp1

uncoupled protein 1

VAT

visceral adipose tissue

VMHvl

ventromedial hypothalamic nucleus

1.
Starling
E.H.
(
1905
)
The Croonian Lectures
.
Lancet
26
,
579
583
2.
Tata
J.R.
(
2005
)
One hundred years of hormones - A new name sparked multidisciplinary research in endocrinology, which shed light on chemical communication in multicellular organisms
.
EMBO Rep.
6
,
490
496
[PubMed]
3.
Scheja
L.
and
Heeren
J.
(
2019
)
The endocrine function of adipose tissues in health and cardiometabolic disease
.
Nat. Rev. Endocrinol.
15
,
507
524
[PubMed]
4.
Stefan
N.
and
Haring
H.U.
(
2013
)
The role of hepatokines in metabolism
.
Nat. Rev. Endocrinol.
9
,
144
152
[PubMed]
5.
Gomarasca
M.
,
Banfi
G.
and
Lombardi
G.
(
2020
)
Myokines: The endocrine coupling of skeletal muscle and bone
.
Adv. Clin. Chem.
94
,
155
218
[PubMed]
6.
Czech
M.P.
(
2017
)
Insulin action and resistance in obesity and type 2 diabetes
.
Nat. Med.
23
,
804
814
[PubMed]
7.
White
M.F.
and
Kahn
C.R.
(
2021
)
Insulin action at a molecular level-100 years of progress
.
Mol. Metab.
52
,
101304
[PubMed]
8.
Flier
J.S.
and
Kahn
C.R.
(
2021
)
Insulin: A pacesetter for the shape of modern biomedical science and the Nobel Prize
.
Mol. Metab.
52
,
101194
[PubMed]
9.
Sims
E.K.
,
Carr
A.L.J.
,
Oram
R.A.
,
DiMeglio
L.A.
and
Evans-Molina
C.
(
2021
)
100 years of insulin: celebrating the past, present and future of diabetes therapy
.
Nat. Med.
27
,
1154
1164
[PubMed]
10.
Cheng
Z.
and
White
M.F.
(
2012
)
The AKTion in non-canonical insulin signaling
.
Nat. Med.
18
,
351
353
[PubMed]
11.
Youle
R.J.
and
Narendra
D.P.
(
2011
)
Mechanisms of mitophagy
.
Nat. Rev. Mol. Cell Biol.
12
,
9
14
[PubMed]
12.
Cheng
Z.
(
2022
)
FoxO transcription factors in mitochondrial homeostasis
.
Biochem. J.
479
,
525
536
[PubMed]
13.
Liu
Y.
,
Lin
H.
,
Jiang
L.
,
Shang
Q.
,
Yin
L.
,
Lin
J.D.
et al.
(
2020
)
Hepatic Slug epigenetically promotes liver lipogenesis, fatty liver disease, and type 2 diabetes
.
J. Clin. Invest.
130
,
2992
3004
[PubMed]
14.
Zheng
L.D.
,
Linarelli
L.E.
,
Liu
L.H.
,
Wall
S.S.
,
Greenawald
M.H.
,
Seidel
R.W.
et al.
(
2015
)
Insulin resistance is associated with epigenetic and genetic regulation of mitochondrial DNA in obese humans
.
Clin. Epigenet.
7
,
1
9
[PubMed]
15.
Liu
Y.
,
Jiang
L.
,
Sun
C.
,
Ireland
N.
,
Shah
Y.M.
,
Liu
Y.
et al.
(
2018
)
Insulin/Snail1 axis ameliorates fatty liver disease by epigenetically suppressing lipogenesis
.
Nat. Commun.
9
,
2751
[PubMed]
16.
Cui
J.
,
Shen
Y.
and
Li
R.
(
2013
)
Estrogen synthesis and signaling pathways during aging: from periphery to brain
.
Trends Mol. Med.
19
,
197
209
[PubMed]
17.
Cooke
P.S.
,
Nanjappa
M.K.
,
Ko
C.
,
Prins
G.S.
and
Hess
R.A.
(
2017
)
Estrogens in male physiology
.
Physiol. Rev.
97
,
995
1043
[PubMed]
18.
De Paoli
M.
,
Zakharia
A.
and
Werstuck
G.H.
(
2021
)
The role of estrogen in insulin resistance: a review of clinical and preclinical data
.
Am. J. Pathol.
191
,
1490
1498
[PubMed]
19.
Uddin
M.
,
Rahman
M.
,
Jakaria
M.
,
Hossain
M.
,
Islam
A.
,
Ahmed
M.
et al.
(
2020
)
Estrogen signaling in Alzheimer's disease: molecular insights and therapeutic targets for Alzheimer's dementia
.
Mol. Neurobiol.
57
,
2654
2670
[PubMed]
20.
Xiang
J.
,
Liu
X.
,
Ren
J.
,
Chen
K.
,
Wang
H.-l.
and
Miao
Y.-y.
(
2019
)
How does estrogen work on autophagy?
Autophagy
15
,
197
211
[PubMed]
21.
Klinge
C.M.
(
2020
)
Estrogenic control of mitochondrial function
.
Redox Biol.
31
,
101435
[PubMed]
22.
Rubinow
K.B.
(
2018
)
An intracrine view of sex steroids, immunity, and metabolic regulation
.
Mol. Metab.
15
,
92
103
[PubMed]
23.
Hampton
T.
(
2020
)
How Targeting Fat Cells' Estrogen Receptors Could Fight Obesity
.
Jama-J. Am. Med. Assoc.
324
,
2146
2146
24.
Ribas
V.
,
Drew
B.G.
,
Zhou
Z.
,
Phun
J.
,
Kalajian
N.Y.
,
Soleymani
T.
et al.
(
2016
)
Skeletal muscle action of estrogen receptor α is critical for the maintenance of mitochondrial function and metabolic homeostasis in females
.
Sci. Transl. Med.
8
,
334ra354
334ra354
25.
Badakhshi
Y.
,
Shao
W.
,
Liu
D.
,
Tian
L.
,
Pang
J.
,
Gu
J.
et al.
(
2021
)
Estrogen-Wnt signaling cascade regulates expression of hepatic fibroblast growth factor 21
.
Am. J. Physiol. Endocrinol. Metab.
321
,
E292
E304
[PubMed]
26.
Elangovan
S.
,
Ramachandran
S.
,
Venkatesan
N.
,
Ananth
S.
,
Gnana-Prakasam
J.P.
,
Martin
P.M.
et al.
(
2011
)
SIRT1 is essential for oncogenic signaling by estrogen/estrogen receptor α in breast cancerpromotion of breast cancer by E2-ERα occurs through SIRT1
.
Cancer Res.
71
,
6654
6664
[PubMed]
27.
Tao
Z.
,
Shi
L.
,
Parke
J.
,
Zheng
L.
,
Gu
W.
,
Dong
X.C.
et al.
(
2021
)
Sirt1 coordinates with ERα to regulate autophagy and adiposity
.
Cell Death Discov.
7
,
1
10
28.
Yan
H.
,
Yang
W.
,
Zhou
F.
,
Li
X.
,
Pan
Q.
,
Shen
Z.
et al.
(
2019
)
Estrogen improves insulin sensitivity and suppresses gluconeogenesis via the transcription factor Foxo1
.
Diabetes
68
,
291
304
[PubMed]
29.
Saltiel
A.R.
(
2021
)
Insulin signaling in health and disease
.
J. Clin. Invest.
131
,
e142241
,
30.
Wang
Y.
,
Viscarra
J.
,
Kim
S.J.
and
Sul
H.S.
(
2015
)
Transcriptional regulation of hepatic lipogenesis
.
Nat. Rev. Mol. Cell Biol.
16
,
678
689
[PubMed]
31.
Ricciardi
S.
,
Boggio
E.M.
,
Grosso
S.
,
Lonetti
G.
,
Forlani
G.
,
Stefanelli
G.
et al.
(
2011
)
Reduced AKT/mTOR signaling and protein synthesis dysregulation in a Rett syndrome animal model
.
Hum. Mol. Genet.
20
,
1182
1196
[PubMed]
32.
Toda
G.
,
Soeda
K.
,
Okazaki
Y.
,
Kobayashi
N.
,
Masuda
Y.
,
Arakawa
N.
et al.
(
2020
)
Insulin- and lipopolysaccharide-mediated signaling in adipose tissue macrophages regulates postprandial glycemia through Akt-mTOR activation
.
Mol. Cell.
79
,
43
+
[PubMed]
33.
Lu
M.
,
Wan
M.
,
Leavens
K.F.
,
Chu
Q.
,
Monks
B.R.
,
Fernandez
S.
et al.
(
2012
)
Insulin regulates liver metabolism in vivo in the absence of hepatic Akt and Foxo1
.
Nat. Med.
18
,
388
395
[PubMed]
34.
Shi
W.
,
Wang
D.
,
Yuan
X.
,
Liu
Y.
,
Guo
X.
,
Li
J.
et al.
(
2019
)
Glucocorticoid receptor-IRS-1 axis controls EMT and the metastasis of breast cancers
.
J. Mol. Cell Biol.
11
,
1042
1055
[PubMed]
35.
Kaleem
A.
,
Javed
S.
,
Rehman
N.
,
Abdullah
R.
,
Iqtedar
M.
,
Aftab
M.N.
et al.
(
2021
)
Phosphorylated and O-GlcNAc modified IRS-1 (Ser1101) and -2 (Ser1149) contribute to human diabetes type II
.
Protein Pept. Lett.
28
,
333
339
[PubMed]
36.
Liu
G.
,
Xiang
T.
,
Wu
Q.F.
and
Wang
W.X.
(
2016
)
Long noncoding RNA H19-derived miR-675 enhances proliferation and invasion via RUNX1 in gastric cancer cells
.
Oncol. Res.
23
,
99
107
[PubMed]
37.
Liu
G.H.
,
Zhao
X.
,
Zhou
J.M.
,
Cheng
X.M.
,
Ye
Z.X.
and
Ji
Z.G.
(
2018
)
LncRNA TP73-AS1 promotes cell proliferation and inhibits cell apoptosis in clear cell renal cell carcinoma through repressing KISS1 expression and inactivation of PI3K/Akt/mTOR signaling pathway
.
Cell. Physiol. Biochem.
48
,
371
384
[PubMed]
38.
Titchenell
P.M.
,
Lazar
M.A.
and
Birnbaum
M.J.
(
2017
)
Unraveling the regulation of hepatic metabolism by insulin
.
Trends Endocrinol. Metab.
28
,
497
505
[PubMed]
39.
Nakae
J.
,
Kitamura
T.
,
Silver
D.L.
and
Accili
D.
(
2001
)
The forkhead transcription factor Foxo1 (Fkhr) confers insulin sensitivity onto glucose-6-phosphatase expression
.
J. Clin. Invest.
108
,
1359
1367
[PubMed]
40.
Lin
H.V.
and
Accili
D.
(
2011
)
Hormonal regulation of hepatic glucose production in health and disease
.
Cell Metab.
14
,
9
19
[PubMed]
41.
Wan
M.
,
Leavens
K.F.
,
Hunter
R.W.
,
Koren
S.
,
von Wilamowitz-Moellendorff
A.
,
Lu
M.
et al.
(
2013
)
A noncanonical, GSK3-independent pathway controls postprandial hepatic glycogen deposition
.
Cell Metab.
18
,
99
105
[PubMed]
42.
Iizuka
K.
,
Bruick
R.K.
,
Liang
G.
,
Horton
J.D.
and
Uyeda
K.
(
2004
)
Deficiency of carbohydrate response element-binding protein (ChREBP) reduces lipogenesis as well as glycolysis
. Proc. Natl. Acad. Sci. U.S.A.
101
,
7281
7286
[PubMed]
43.
Li
S.
,
Brown
M.S.
and
Goldstein
J.L.
(
2010
)
Bifurcation of insulin signaling pathway in rat liver: mTORC1 required for stimulation of lipogenesis, but not inhibition of gluconeogenesis
.
Proc. Natl. Acad. Sci. U.S.A.
107
,
3441
3446
[PubMed]
44.
Porstmann
T.
,
Santos
C.R.
,
Griffiths
B.
,
Cully
M.
,
Wu
M.
,
Leevers
S.
et al.
(
2008
)
SREBP activity is regulated by mTORC1 and contributes to Akt-dependent cell growth
.
Cell Metab.
8
,
224
236
[PubMed]
45.
Naito
T.
,
Kuma
A.
and
Mizushima
N.
(
2013
)
Differential contribution of insulin and amino acids to the mTORC1-autophagy pathway in the liver and muscle
.
J. Biol. Chem.
288
,
21074
21081
[PubMed]
46.
James
H.A.
,
O'Neill
B.T.
and
Nair
K.S.
(
2017
)
Insulin regulation of proteostasis and clinical implications
.
Cell Metab.
26
,
310
323
[PubMed]
47.
O'Neill
B.T.
,
Lauritzen
H.P.
,
Hirshman
M.F.
,
Smyth
G.
,
Goodyear
L.J.
and
Kahn
C.R.
(
2015
)
Differential role of insulin/IGF-1 receptor signaling in muscle growth and glucose homeostasis
.
Cell Rep.
11
,
1220
1235
[PubMed]
48.
Zhang
X.
,
Xu
D.
,
Chen
M.
,
Wang
Y.
,
He
L.
,
Wang
L.
et al.
(
2021
)
Impacts of selected dietary nutrient intakes on skeletal muscle insulin sensitivity and applications to early prevention of Type 2 diabetes
.
Adv. Nutr.
12
,
1305
1316
[PubMed]
49.
Milan
G.
,
Romanello
V.
,
Pescatore
F.
,
Armani
A.
,
Paik
J.H.
,
Frasson
L.
et al.
(
2015
)
Regulation of autophagy and the ubiquitin-proteasome system by the FoxO transcriptional network during muscle atrophy
.
Nat. Commun.
6
,
6670
[PubMed]
50.
Møller
L.L.
,
Jaurji
M.
,
Kjøbsted
R.
,
Joseph
G.A.
,
Madsen
A.B.
,
Knudsen
J.R.
et al.
(
2020
)
Insulin‐stimulated glucose uptake partly relies on p21‐activated kinase (PAK) 2, but not PAK1, in mouse skeletal muscle
.
J. Physiol.
598
,
5351
5377
[PubMed]
51.
Sylow
L.
,
Jensen
T.E.
,
Kleinert
M.
,
Højlund
K.
,
Kiens
B.
,
Wojtaszewski
J.
et al.
(
2013
)
Rac1 signaling is required for insulin-stimulated glucose uptake and is dysregulated in insulin-resistant murine and human skeletal muscle
.
Diabetes
62
,
1865
1875
[PubMed]
52.
Turner
M.C.
,
Martin
N.R.W.
,
Player
D.J.
,
Ferguson
R.A.
,
Wheeler
P.
,
Green
C.J.
et al.
(
2020
)
Characterising hyperinsulinemia-induced insulin resistance in human skeletal muscle cells
.
J. Mol. Endocrinol.
64
,
125
132
[PubMed]
53.
Lee
J.H.
,
Jahrling
J.B.
,
Denner
L.
and
Dineley
K.T.
(
2018
)
Targeting insulin for Alzheimer's disease: mechanisms, status and potential directions
.
J. Alzheimers Dis.
64
,
S427
S453
[PubMed]
54.
Hölscher
C.
(
2020
)
Brain insulin resistance: role in neurodegenerative disease and potential for targeting
.
Expert Opin. Investig. Drugs
29
,
333
348
[PubMed]
55.
Szendroedi
J.
,
Phielix
E.
and
Roden
M.
(
2012
)
The role of mitochondria in insulin resistance and type 2 diabetes mellitus
.
Nat. Rev. Endocrinol.
8
,
92
103
56.
Brunetta
H.S.
,
Petrick
H.L.
,
Vachon
B.
,
Nunes
E.A.
and
Holloway
G.P.
(
2021
)
Insulin rapidly increases skeletal muscle mitochondrial ADP sensitivity in the absence of a high lipid environment
.
Biochem. J.
478
,
2539
2553
[PubMed]
57.
Shannon
C.E.
,
Ragavan
M.
,
Palavicini
J.P.
,
Fourcaudot
M.
,
Bakewell
T.M.
,
Valdez
I.A.
et al.
(
2021
)
Insulin resistance is mechanistically linked to hepatic mitochondrial remodeling in non-alcoholic fatty liver disease
.
Mol. Metab.
45
,
101154
[PubMed]
58.
Suomalainen
A.
and
Battersby
B.J.
(
2018
)
Mitochondrial diseases: the contribution of organelle stress responses to pathology
.
Nat. Rev. Mol. Cell Biol.
19
,
77
92
[PubMed]
59.
Rowe
G.C.
,
El-Khoury
R.
,
Patten
I.S.
,
Rustin
P.
and
Arany
Z.
(
2012
)
PGC-1α is dispensable for exercise-induced mitochondrial biogenesis in skeletal muscle
.
PLoS ONE
7
,
e41817
[PubMed]
60.
Wilson
L.
,
Yang
Q.
,
Szustakowski
J.D.
,
Gullicksen
P.S.
and
Halse
R.
(
2007
)
Pyruvate induces mitochondrial biogenesis by a PGC-1 alpha-independent mechanism
.
Am. J. Physiol. Cell Physiol.
292
,
C1599
C1605
[PubMed]
61.
Cheng
Z.
,
Guo
S.
,
Copps
K.
,
Dong
X.
,
Kollipara
R.
,
Rodgers
J.T.
et al.
(
2009
)
Foxo1 integrates insulin signaling with mitochondrial function in the liver
.
Nat. Med.
15
,
1307
1311
[PubMed]
62.
Wang
K.
,
Long
B.
,
Jiao
J.Q.
,
Wang
J.X.
,
Liu
J.P.
,
Li
Q.
et al.
(
2012
)
miR-484 regulates mitochondrial network through targeting Fis1
.
Nat. Commun.
3
,
1
9
63.
Li
W.
,
Du
M.
,
Wang
Q.
,
Ma
X.
,
Wu
L.
,
Guo
F.
et al.
(
2017
)
FoxO1 Promotes Mitophagy in the Podocytes of Diabetic Male Mice via the PINK1/Parkin Pathway
.
Endocrinology
158
,
2155
2167
[PubMed]
64.
Song
D.
,
Ma
J.
,
Chen
L.
,
Guo
C.
,
Zhang
Y.
,
Chen
T.
et al.
(
2017
)
FOXO3 promoted mitophagy via nuclear retention induced by manganese chloride in SH-SY5Y cells
.
Metallomics
9
,
1251
1259
[PubMed]
65.
Chaanine
A.H.
,
Kohlbrenner
E.
,
Gamb
S.I.
,
Guenzel
A.J.
,
Klaus
K.
,
Fayyaz
A.U.
et al.
(
2016
)
FOXO3a regulates BNIP3 and modulates mitochondrial calcium, dynamics, and function in cardiac stress
.
Am. J. Physiol. Heart Circ. Physiol.
311
,
H1540
H1559
[PubMed]
66.
Chaanine
A.H.
,
Jeong
D.
,
Liang
L.
,
Chemaly
E.R.
,
Fish
K.
,
Gordon
R.E.
et al.
(
2012
)
JNK modulates FOXO3a for the expression of the mitochondrial death and mitophagy marker BNIP3 in pathological hypertrophy and in heart failure
.
Cell Death Dis.
3
,
265
[PubMed]
67.
Dashty
M.
(
2013
)
A quick look at biochemistry: carbohydrate metabolism
.
Clin. Biochem.
46
,
1339
1352
[PubMed]
68.
Fernandez-Marcos
P.J.
and
Auwerx
J.
(
2011
)
Regulation of PGC-1alpha, a nodal regulator of mitochondrial biogenesis
.
Am. J. Clin. Nutr.
93
,
884S
890S
[PubMed]
69.
Rodgers
J.T.
,
Haas
W.
,
Gygi
S.P.
and
Puigserver
P.
(
2010
)
Cdc2-like kinase 2 is an insulin-regulated suppressor of hepatic gluconeogenesis
.
Cell Metab.
11
,
23
34
[PubMed]
70.
Herzig
S.
,
Hedrick
S.
,
Morantte
I.
,
Koo
S.-H.
,
Galimi
F.
and
Montminy
M.
(
2003
)
CREB controls hepatic lipid metabolism through nuclear hormone receptor PPAR-γ
.
Nature
426
,
190
193
[PubMed]
71.
Yoon
J.C.
,
Puigserver
P.
,
Chen
G.X.
,
Donovan
J.
,
Wu
Z.D.
,
Rhee
J.
et al.
(
2001
)
Control of hepatic gluconeogenesis through the transcriptional coactivator PGC-1
.
Nature
413
,
131
138
[PubMed]
72.
Kuzuya
T.
,
Nakagawa
S.
,
Satoh
J.
,
Kanazawa
Y.
,
Iwamoto
Y.
,
Kobayashi
M.
et al.
(
2002
)
Report of the Committee on the classification and diagnostic criteria of diabetes mellitus
.
Diabetes Res. Clin. Pract.
55
,
65
85
[PubMed]
73.
Federation
I.
(
2021
)
IDF Diabetes Atlas Eighth edition 2017. International Diabetes Federation
.
IDF Diabetes Atlas
8th edn.
Brussels, Belgium
International Diabetes Federation
,
2017
74.
Mathieu
C.
,
Gillard
P.
and
Benhalima
K.
(
2017
)
Insulin analogues in type 1 diabetes mellitus: getting better all the time
.
Nat. Rev. Endocrinol.
13
,
385
399
[PubMed]
75.
Polyzos
S.A.
and
Mantzoros
C.S.
(
2021
)
Diabetes mellitus: 100 years since the discovery of insulin
.
Metab.-Clin. Exp.
118
,
154737
76.
Atkinson
M.A.
,
Eisenbarth
G.S.
and
Michels
A.W.
(
2014
)
Type 1 diabetes
.
Lancet North Am. Ed.
383
,
69
82
77.
Beale
E.G.
(
2013
)
Insulin signaling and insulin resistance
.
J. Investig. Med.
61
,
11
14
[PubMed]
78.
White
M.F.
(
2003
)
Insulin signaling in health and disease
.
Science
302
,
1710
1711
[PubMed]
79.
Cusi
K.
,
Sanyal
A.J.
,
Zhang
S.
,
Hartman
M.L.
,
Bue-Valleskey
J.M.
,
Hoogwerf
B.J.
et al.
(
2017
)
Non-alcoholic fatty liver disease (NAFLD) prevalence and its metabolic associations in patients with type 1 diabetes and type 2 diabetes
.
Diabetes Obes. Metab.
19
,
1630
1634
[PubMed]
80.
de Mello
V.D.
,
Matte
A.
,
Perfilyev
A.
,
Mannisto
V.
,
Ronn
T.
,
Nilsson
E.
et al.
(
2017
)
Human liver epigenetic alterations in non-alcoholic steatohepatitis are related to insulin action
.
Epigenetics
12
,
287
295
[PubMed]
81.
Cláudia
B.S.
,
de Carli
L.A.
,
Pioner
S.R.
,
Fantinelli
M.
,
Gobbato
S.S.
,
Bassols
G.F.
et al.
(
2018
)
Impact of diabetes mellitus and insulin on nonalcoholic fatty liver disease in the morbidly obese
.
Ann. Hepatol.
17
,
585
591
[PubMed]
82.
Moh Moh
M.A.
,
Jung
C.H.
,
Lee
B.
,
Choi
D.
,
Kim
B.Y.
,
Kim
C.H.
et al.
(
2019
)
Association of glucagon-to-insulin ratio and nonalcoholic fatty liver disease in patients with type 2 diabetes mellitus
.
Diab. Vasc. Dis. Res.
16
,
186
195
[PubMed]
83.
Kubota
N.
,
Kubota
T.
,
Kajiwara
E.
,
Iwamura
T.
,
Kumagai
H.
,
Watanabe
T.
et al.
(
2016
)
Differential hepatic distribution of insulin receptor substrates causes selective insulin resistance in diabetes and obesity
.
Nat. Commun.
7
,
12977
[PubMed]
84.
Smith
G.I.
,
Shankaran
M.
,
Yoshino
M.
,
Schweitzer
G.G.
,
Chondronikola
M.
,
Beals
J.W.
et al.
(
2020
)
Insulin resistance drives hepatic de novo lipogenesis in nonalcoholic fatty liver disease
.
J. Clin. Invest.
130
,
1453
1460
[PubMed]
85.
Luukkonen
P.K.
,
Sädevirta
S.
,
Zhou
Y.
,
Kayser
B.
,
Ali
A.
,
Ahonen
L.
et al.
(
2018
)
Saturated fat is more metabolically harmful for the human liver than unsaturated fat or simple sugars
.
Diabetes Care.
41
,
1732
1739
[PubMed]
86.
Ter Horst
K.W.
,
Vatner
D.F.
,
Zhang
D.
,
Cline
G.W.
,
Ackermans
M.T.
,
Nederveen
A.J.
et al.
(
2021
)
Hepatic insulin resistance is not pathway selective in humans with nonalcoholic fatty liver disease
.
Diabetes Care
44
,
489
498
[PubMed]
87.
Broussard
J.L.
,
Bergman
R.N.
,
Bediako
I.A.
,
Paszkiewicz
R.L.
,
Iyer
M.S.
and
Kolka
C.M.
(
2018
)
Insulin access to skeletal muscle is preserved in obesity induced by polyunsaturated diet
.
Obesity
26
,
119
125
[PubMed]
88.
Wu
H.-K.
,
Zhang
Y.
,
Cao
C.-M.
,
Hu
X.
,
Fang
M.
,
Yao
Y.
et al.
(
2019
)
Glucose-sensitive myokine/cardiokine MG53 regulates systemic insulin response and metabolic homeostasis
.
Circulation
139
,
901
914
[PubMed]
89.
Zhuang
L.
,
Bassel-Duby
R.
and
Olson
E.N.
(
2019
)
Secreted MG53 from striated muscle impairs systemic insulin sensitivity
.
Am. Heart Assoc.
,
139
915
917
90.
Sugimoto
K.
,
Ikegami
H.
,
Takata
Y.
,
Katsuya
T.
,
Fukuda
M.
,
Akasaka
H.
et al.
(
2021
)
Glycemic control and insulin improve muscle mass and gait speed in Type 2 Diabetes: The MUSCLES-DM Study
.
J. Am. Med. Dir. Assoc.
22
,
834e831
838e831
[PubMed]
91.
Bouchi
R.
,
Fukuda
T.
,
Takeuchi
T.
,
Nakano
Y.
,
Murakami
M.
,
Minami
I.
et al.
(
2017
)
Insulin treatment attenuates decline of muscle mass in Japanese patients with type 2 diabetes
.
Calcif. Tissue Int.
101
,
1
8
[PubMed]
92.
Kakehi
S.
,
Tamura
Y.
,
Ikeda
S.I.
,
Kaga
N.
,
Taka
H.
,
Ueno
N.
et al.
(
2021
)
Short-term physical inactivity induces diacylglycerol accumulation and insulin resistance in muscle via lipin1 activation
.
Am. J. Physiol. Endocrinol. Metab.
321
,
E766
E781
[PubMed]
93.
Agrawal
R.
,
Reno
C.M.
,
Sharma
S.
,
Christensen
C.
,
Huang
Y.
and
Fisher
S.J.
(
2021
)
Insulin action in the brain regulates both central and peripheral functions
.
Am. J. Physiol.-Endocrinol. Metab.
321
,
E156
E163
[PubMed]
94.
Ekblad
L.L.
,
Johansson
J.
,
Helin
S.
,
Viitanen
M.
,
Laine
H.
,
Puukka
P.
et al.
(
2018
)
Midlife insulin resistance, APOE genotype, and late-life brain amyloid accumulation
.
Neurology
90
,
e1150
e1157
[PubMed]
95.
Mittal
K.
and
Katare
D.P.
(
2016
)
Shared links between type 2 diabetes mellitus and Alzheimer's disease: a review
.
Diab. Metabolic Syndrome: Clin. Res. Rev.
10
,
S144
S149
96.
Beeri
M.S.
,
Schmeidler
J.
,
Silverman
J.M.
,
Gandy
S.
,
Wysocki
M.
,
Hannigan
C.M.
et al.
(
2008
)
Insulin in combination with other diabetes medication is associated with less Alzheimer neuropathology
.
Neurology
71
,
750
757
[PubMed]
97.
Sonnen
J.A.
,
Larson
E.B.
,
Brickell
K.
,
Crane
P.K.
,
Woltjer
R.
,
Montine
T.J.
et al.
(
2009
)
Different Patterns of Cerebral Injury in Dementia With or Without Diabetes
.
Arch. Neurol.
66
,
315
322
[PubMed]
98.
Kellar
D.
and
Craft
S.
(
2020
)
Brain insulin resistance in Alzheimer's disease and related disorders: mechanisms and therapeutic approaches
.
Lancet Neurol.
19
,
758
766
[PubMed]
99.
Reger
M.A.
,
Watson
G.S.
,
Frey
W.H.
2nd
,
Baker
L.D.
,
Cholerton
B.
,
Keeling
M.L.
et al.
(
2006
)
Effects of intranasal insulin on cognition in memory-impaired older adults: modulation by APOE genotype
.
Neurobiol. Aging
27
,
451
458
[PubMed]
100.
Reger
M.A.
,
Watson
G.S.
,
Green
P.S.
,
Baker
L.D.
,
Cholerton
B.
,
Fishel
M.A.
et al.
(
2008
)
Intranasal insulin administration dose-dependently modulates verbal memory and plasma amyloid-beta in memory-impaired older adults
.
J. Alzheimers Dis.
13
,
323
331
[PubMed]
101.
Craft
S.
,
Raman
R.
,
Chow
T.W.
,
Rafii
M.S.
,
Sun
C.K.
,
Rissman
R.A.
et al.
(
2020
)
Safety, efficacy, and feasibility of intranasal insulin for the treatment of mild cognitive impairment and Alzheimer disease dementia: a randomized clinical trial
.
JAMA Neurol.
77
,
1099
1109
[PubMed]
102.
Valla
V.
(
2010
)
Therapeutics of diabetes mellitus: focus on insulin analogues and insulin pumps
.
Exp. Diab. Res.
2010
,
178372
[PubMed]
103.
Kazakos
K.
(
2011
)
Incretin effect: GLP-1, GIP, DPP4
.
Diabetes Res. Clin. Pract.
93
,
S32
S36
[PubMed]
104.
Frias
J.P.
,
Bastyr
E.J.
III
,
Vignati
L.
,
Tschop
M.H.
,
Schmitt
C.
,
Owen
K.
et al.
(
2017
)
The sustained effects of a dual GIP/GLP-1 receptor agonist, NNC0090-2746, in patients with Type 2 diabetes
.
Cell Metab.
26
,
343e342
352e342
[PubMed]
105.
Kavinilavu
L.
(
2022
)
Mounjaro (Tirzepatide): a review
.
Res. Rev.: Manag. Cardiovasc. Orthopedic Compl. (e-ISSN: 2582-5739)
,
4
24
27
106.
Cypess
A.M.
,
Weiner
L.S.
,
Roberts-Toler
C.
,
Franquet Elia
E.
et al.
(
2015
)
Activation of human brown adipose tissue by a beta3-adrenergic receptor agonist
.
Cell Metab.
21
,
33
38
[PubMed]
107.
Cero
C.
,
Lea
H.J.
,
Zhu
K.Y.
,
Shamsi
F.
,
Tseng
Y.H.
and
Cypess
A.M.
(
2021
)
beta3-Adrenergic receptors regulate human brown/beige adipocyte lipolysis and thermogenesis
.
JCI Insight
6
,
e139160
[PubMed]
108.
O'Mara
A.E.
,
Johnson
J.W.
,
Linderman
J.D.
,
Brychta
R.J.
,
McGehee
S.
,
Fletcher
L.A.
et al.
(
2020
)
Chronic mirabegron treatment increases human brown fat, HDL cholesterol, and insulin sensitivity
.
J. Clin. Invest.
130
,
2209
2219
[PubMed]
109.
Ferguson
D.
and
Finck
B.N.
(
2021
)
Emerging therapeutic approaches for the treatment of NAFLD and type 2 diabetes mellitus
.
Nat. Rev. Endocrinol.
17
,
484
495
[PubMed]
110.
De Paoli
M.
and
Werstuck
G.H.
(
2020
)
Role of estrogen in Type 1 and Type 2 diabetes mellitus: a review of clinical and preclinical data
.
Can J. Diab.
44
,
448
452
[PubMed]
111.
Tramunt
B.
,
Smati
S.
,
Grandgeorge
N.
,
Lenfant
F.
,
Arnal
J.F.
,
Montagner
A.
et al.
(
2020
)
Sex differences in metabolic regulation and diabetes susceptibility
.
Diabetologia
63
,
453
461
[PubMed]
112.
Yang
X.P.
and
Reckelhoff
J.F.
(
2011
)
Estrogen, hormonal replacement therapy and cardiovascular disease
.
Curr. Opin. Nephrol. Hypertens.
20
,
133
138
[PubMed]
113.
Anand
S.S.
,
Islam
S.
,
Rosengren
A.
,
Franzosi
M.G.
,
Steyn
K.
,
Yusufali
A.H.
et al.
(
2008
)
Risk factors for myocardial infarction in women and men: insights from the INTERHEART study
.
Eur. Heart J.
29
,
932
940
[PubMed]
114.
Pan
J.J.
and
Fallon
M.B.
(
2014
)
Gender and racial differences in nonalcoholic fatty liver disease
.
World J. Hepatol.
6
,
274
283
[PubMed]
115.
Chen
K.L.
and
Madak-Erdogan
Z.
(
2018
)
Estrogens and female liver health
.
Steroids
133
,
38
43
[PubMed]
116.
DiStefano
J.K.
(
2020
)
NAFLD and NASH in postmenopausal women: implications for diagnosis and treatment
.
Endocrinology
161
,
bqaa134
[PubMed]
117.
Yan
H.
,
Yang
W.
,
Zhou
F.
,
Pan
Q.
,
Allred
K.
,
Allred
C.
et al.
(
2022
)
Estrogen protects cardiac function and energy metabolism in dilated cardiomyopathy induced by loss of cardiac IRS1 and IRS2
.
Circ. Heart Fail.
15
,
e008758
[PubMed]
118.
Liebmann
M.
,
Asuaje Pfeifer
M.
,
Grupe
K.
et al.
(
2022
)
Estradiol (E2) improves glucose-stimulated insulin secretion and stabilizes GDM progression in a prediabetic mouse model
.
Int. J. Mol. Sci.
23
,
6693
[PubMed]
119.
Ruggiero
R.J.
and
Likis
F.E.
(
2002
)
Estrogen: physiology, pharmacology, and formulations for replacement therapy
.
J. Midwifery Women's Health
47
,
130
138
120.
Huether
S.E.
and
McCance
K.L.
(
2019
)
Understanding Pathophysiology-E-Book
,
Elsevier Health Sciences
121.
Li
J.
,
Papadopoulos
V.
and
Vihma
V.
(
2015
)
Steroid biosynthesis in adipose tissue
.
Steroids
103
,
89
104
[PubMed]
122.
Hetemäki
N.
,
Mikkola
T.S.
,
Tikkanen
M.J.
,
Wang
F.
,
Hämäläinen
E.
,
Turpeinen
U.
et al.
(
2021
)
Adipose tissue estrogen production and metabolism in premenopausal women
.
J. Steroid Biochem. Mol. Biol.
209
,
105849
[PubMed]
123.
Hewitt
S.C.
and
Korach
K.S.
(
2018
)
Estrogen receptors: new directions in the new millennium
.
Endocr. Rev.
39
,
664
675
[PubMed]
124.
Olde
B.
and
Leeb-Lundberg
L.M.
(
2009
)
GPR30/GPER1: searching for a role in estrogen physiology
.
Trends Endocrinol. Metab.
20
,
409
416
[PubMed]
125.
Gourdy
P.
,
Guillaume
M.
,
Fontaine
C.
,
Adlanmerini
M.
,
Montagner
A.
,
Laurell
H.
et al.
(
2018
)
Estrogen receptor subcellular localization and cardiometabolism
.
Mol. Metab.
15
,
56
69
[PubMed]
126.
Collins
B.C.
,
Laakkonen
E.K.
and
Lowe
D.A.
(
2019
)
Aging of the musculoskeletal system: How the loss of estrogen impacts muscle strength
.
Bone
123
,
137
144
[PubMed]
127.
Ikeda
K.
,
Horie-Inoue
K.
and
Inoue
S.
(
2019
)
Functions of estrogen and estrogen receptor signaling on skeletal muscle
.
J. Steroid Biochem. Mol. Biol.
191
,
105375
[PubMed]
128.
Bagit
A.
,
Hayward
G.C.
and
MacPherson
R.E.K.
(
2021
)
Exercise and estrogen: common pathways in Alzheimer's disease pathology
.
Am. J. Physiol. Endocrinol. Metab.
321
,
E164
E168
[PubMed]
129.
Beeri
M.S.
and
Sonnen
J.
(
2016
)
Brain BDNF expression as a biomarker for cognitive reserve against Alzheimer disease progression
, pp.
702
703
,
AAN Enterprises
130.
Vang
P.
,
Baumann
C.W.
,
Barok
R.
,
Larson
A.A.
,
Dougherty
B.J.
and
Lowe
D.A.
(
2021
)
Impact of estrogen deficiency on diaphragm and leg muscle contractile function in female mdx mice
.
PloS ONE
16
,
e0249472
[PubMed]
131.
Sipila
S.
,
Taaffe
D.R.
,
Cheng
S.
,
Puolakka
J.
,
Toivanen
J.
and
Suominen
H.
(
2001
)
Effects of hormone replacement therapy and high-impact physical exercise on skeletal muscle in post-menopausal women: a randomized placebo-controlled study
.
Clin. Sci. (Lond.)
101
,
147
157
[PubMed]
132.
Hansen
M.
,
Skovgaard
D.
,
Reitelseder
S.
,
Holm
L.
,
Langbjerg
H.
and
Kjaer
M.
(
2012
)
Effects of estrogen replacement and lower androgen status on skeletal muscle collagen and myofibrillar protein synthesis in postmenopausal women
.
J. Gerontol. A Biol. Sci. Med. Sci.
67
,
1005
1013
[PubMed]
133.
Toth
M.J.
,
Poehlman
E.T.
,
Matthews
D.E.
,
Tchernof
A.
and
MacCoss
M.J.
(
2001
)
Effects of estradiol and progesterone on body composition, protein synthesis, and lipoprotein lipase in rats
.
Am. J. Physiol. Endocrinol. Metab.
280
,
E496
E501
[PubMed]
134.
Kamanga-Sollo
E.
,
Thornton
K.
,
White
M.
and
Dayton
W.
(
2017
)
Role of G protein-coupled estrogen receptor-1 in estradiol 17β-induced alterations in protein synthesis and protein degradation rates in fused bovine satellite cell cultures
.
Domest. Anim. Endocrinol.
58
,
90
96
[PubMed]
135.
Kamanga-Sollo
E.
,
White
M.
,
Hathaway
M.
,
Weber
W.
and
Dayton
W.
(
2010
)
Effect of estradiol-17β on protein synthesis and degradation rates in fused bovine satellite cell cultures
.
Domest. Anim. Endocrinol.
39
,
54
62
[PubMed]
136.
Tao
Z.
,
Zheng
L.D.
,
Smith
C.
,
Luo
J.
,
Robinson
A.
,
Almeida
F.A.
et al.
(
2018
)
Estradiol signaling mediates gender difference in visceral adiposity via autophagy
.
Cell Death Dis.
9
,
309
[PubMed]
137.
Jazbutyte
V.
,
Kehl
F.
,
Neyses
L.
and
Pelzer
T.
(
2009
)
Estrogen receptor alpha interacts with 17beta-hydroxysteroid dehydrogenase type 10 in mitochondria
.
Biochem. Biophys. Res. Commun.
384
,
450
454
[PubMed]
138.
Pedram
A.
,
Razandi
M.
,
Wallace
D.C.
and
Levin
E.R.
(
2006
)
Functional estrogen receptors in the mitochondria of breast cancer cells
.
Mol. Biol. Cell.
17
,
2125
2137
[PubMed]
139.
Nagai
S.
,
Ikeda
K.
,
Horie-Inoue
K.
,
Takeda
S.
and
Inoue
S.
(
2018
)
Estrogen signaling increases nuclear receptor subfamily 4 group A member 1 expression and energy production in skeletal muscle cells
.
Endocr. J.
65
,
1209
1218
[PubMed]
140.
Singh
R.
,
Wang
Y.
,
Xiang
Y.
,
Tanaka
K.E.
,
Gaarde
W.A.
and
Czaja
M.J.
(
2009
)
Differential effects of JNK1 and JNK2 inhibition on murine steatohepatitis and insulin resistance
.
Hepatology
49
,
87
96
[PubMed]
141.
Galmes-Pascual
B.M.
,
Martinez-Cignoni
M.R.
,
Moran-Costoya
A.
,
Bauza-Thorbrugge
M.
,
Sbert-Roig
M.
,
Valle
A.
et al.
(
2020
)
17beta-estradiol ameliorates lipotoxicity-induced hepatic mitochondrial oxidative stress and insulin resistance
.
Free Radic. Biol. Med.
150
,
148
160
[PubMed]
142.
Zhou
Z.
,
Moore
T.M.
,
Drew
B.G.
,
Ribas
V.
,
Wanagat
J.
,
Civelek
M.
et al.
(
2020
)
Estrogen receptor alpha controls metabolism in white and brown adipocytes by regulating Polg1 and mitochondrial remodeling
.
Sci. Transl. Med.
12
,
eaax8096
[PubMed]
143.
Bauzá-Thorbrügge
M.
,
Rodriguez-Cuenca
S.
,
Vidal-Puig
A.
,
Galmes-Pascual
B.M.
,
Sbert-Roig
M.
,
Gianotti
M.
et al.
(
2019
)
GPER and ERα mediate estradiol enhancement of mitochondrial function in inflamed adipocytes through a PKA dependent mechanism
.
J. Steroid Biochem. Mol. Biol.
185
,
256
267
[PubMed]
144.
,
Mol Metab
,
34
,
1
15
Iñigo
M.R.
,
Amorese
A.J.
,
Tarpey
M.D.
,
Balestrieri
N.P.
,
Jones
K.G.
et al.
(
2020
)
Estrogen receptor-α in female skeletal muscle is not required for regulation of muscle insulin sensitivity and mitochondrial regulation
145.
Karastergiou
K.
,
Smith
S.R.
,
Greenberg
A.S.
and
Fried
S.K.
(
2012
)
Sex differences in human adipose tissues - the biology of pear shape
.
Biol. Sex Differ.
3
,
13
[PubMed]
146.
Kaplan
J.R.
and
Manuck
S.B.
(
2008
)
Ovarian dysfunction and the premenopausal origins of coronary heart disease
.
Menopause-the J.e North Am. Menopause Soc.
15
,
768
776
[PubMed]
147.
Archer
D.F.
(
2009
)
Premature menopause increases cardiovascular risk
.
Climacteric
12
,
26
31
[PubMed]
148.
Jacobsen
B.K.
,
Nilssen
S.
,
Heuch
I.
and
Kvåle
G.
(
1997
)
Does age at natural menopause affect mortality from ischemic heart disease?
J. Clin. Epidemiol.
50
,
475
479
[PubMed]
149.
Cooper
G.S.
and
Sandler
D.P.
(
1998
)
Age at natural menopause and mortality
.
Ann. Epidemiol.
8
,
229
235
[PubMed]
150.
Herrera-Lopez
E.E.
,
Castelan-Martinez
O.D.
,
Suarez-Sanchez
F.
,
Gomez-Zamudio
J.H.
,
Peralta-Romero
J.J.
,
Cruz
M.
et al.
(
2018
)
The rs1256031 of estrogen receptor β gene is associated with type 2 diabetes
.
Diab. Metabolic Syndrome: Clin. Res. Rev.
12
,
631
633
151.
Kumagai
H.
,
Miyamoto-Mikami
E.
,
Hirata
K.
,
Kikuchi
N.
,
Kamiya
N.
,
Hoshikawa
S.
et al.
(
2019
)
ESR1 rs2234693 Polymorphism Is Associated with Muscle Injury and Muscle Stiffness
.
Med. Sci. Sports Exerc.
51
,
19
26
[PubMed]
152.
Song
Y.J.
,
Li
S.R.
,
Li
X.W.
,
Chen
X.
,
Wei
Z.X.
,
Liu
Q.S.
et al.
(
2020
)
The Effect of Estrogen Replacement Therapy on Alzheimer's Disease and Parkinson's Disease in Postmenopausal Women: A Meta-Analysis
.
Front. Neurosci.
14
,
157
[PubMed]
153.
Lee
Y.H.
,
Cha
J.
,
Chung
S.J.
,
Yoo
H.S.
,
Sohn
Y.H.
,
Ye
B.S.
et al.
(
2019
)
Beneficial effect of estrogen on nigrostriatal dopaminergic neurons in drug-naive postmenopausal Parkinson's disease
.
Sci. Rep.
9
,
10531
[PubMed]
154.
Mérot
Y.
,
Métivier
R.
,
Penot
G.
,
Manu
D.
,
Saligaut
C.
,
Gannon
F.
et al.
(
2004
)
The relative contribution exerted by AF-1 and AF-2 transactivation functions in estrogen receptor α transcriptional activity depends upon the differentiation stage of the cell
.
J. Biol. Chem.
279
,
26184
26191
[PubMed]
155.
Hinton
A.O.
Jr
,
He
Y.
,
Xia
Y.
,
Xu
P.
,
Yang
Y.
,
Saito
K.
et al.
(
2016
)
Estrogen receptor-α in the medial amygdala prevents stress-induced elevations in blood pressure in females
.
Hypertension
67
,
1321
1330
[PubMed]
156.
Darblade
B.
,
Pendaries
C.
,
Krust
A.
,
Dupont
S.
,
Fouque
M.-J.
,
Rami
J.
et al.
(
2002
)
Estradiol alters nitric oxide production in the mouse aorta through the α-, but not β-, estrogen receptor
.
Circ. Res.
90
,
413
419
[PubMed]
157.
Bolego
C.
,
Cignarella
A.
,
Sanvito
P.
,
Pelosi
V.
,
Pellegatta
F.
,
Puglisi
L.
et al.
(
2005
)
The acute estrogenic dilation of rat aorta is mediated solely by selective estrogen receptor-α agonists and is abolished by estrogen deprivation
.
J. Pharmacol. Exp. Ther.
313
,
1203
1208
[PubMed]
158.
Krug
R.
,
Beier
L.
,
Lammerhofer
M.
and
Hallschmid
M.
(
2022
)
Distinct and convergent beneficial effects of estrogen and insulin on cognitive function in healthy young men
.
J. Clin. Endocrinol. Metab.
107
,
e582
e593
[PubMed]
159.
Heine
P.
,
Taylor
J.
,
Iwamoto
G.
,
Lubahn
D.
and
Cooke
P.
(
2000
)
Increased adipose tissue in male and female estrogen receptor-α knockout mice
.
Proc. Natl. Acad. Sci.
97
,
12729
12734
160.
Bryzgalova
G.
,
Gao
H.
,
Ahrén
B.
,
Zierath
J.
,
Galuska
D.
,
Steiler
T.
et al.
(
2006
)
Evidence that oestrogen receptor-α plays an important role in the regulation of glucose homeostasis in mice: insulin sensitivity in the liver
.
Diabetologia
49
,
588
597
[PubMed]
161.
Chaiyasing
R.
,
Sugiura
A.
,
Ishikawa
T.
,
Ojima
K.
,
Warita
K.
and
Hosaka
Y.Z.
(
2021
)
Estrogen modulates the skeletal muscle regeneration process and myotube morphogenesis: morphological analysis in mice with a low estrogen status
.
J. Vet. Med. Sci.
83
,
1812
1819
[PubMed]
162.
Collins
B.C.
,
Mader
T.L.
,
Cabelka
C.A.
,
Inigo
M.R.
,
Spangenburg
E.E.
and
Lowe
D.A.
(
2018
)
Deletion of estrogen receptor alpha in skeletal muscle results in impaired contractility in female mice
.
J. Appl. Physiol. (1985)
124
,
980
992
[PubMed]
163.
Winn
N.C.
,
Jurrissen
T.J.
,
Grunewald
Z.I.
,
Cunningham
R.P.
,
Woodford
M.L.
,
Kanaley
J.A.
et al.
(
2019
)
Estrogen receptor-α signaling maintains immunometabolic function in males and is obligatory for exercise-induced amelioration of nonalcoholic fatty liver
.
Am. J. Physiol.-Endoc. M.
316
,
E156
E167
164.
Meda
C.
,
Barone
M.
,
Mitro
N.
,
Lolli
F.
,
Pedretti
S.
,
Caruso
D.
et al.
(
2020
)
Hepatic ERalpha accounts for sex differences in the ability to cope with an excess of dietary lipids
.
Mol. Metab.
32
,
97
108
[PubMed]
165.
Lonardo
A.
,
Nascimbeni
F.
,
Ballestri
S.
,
Fairweather
D.
,
Win
S.
,
Than
T.A.
et al.
(
2019
)
Sex Differences in Nonalcoholic Fatty Liver Disease: State of the Art and Identification of Research Gaps
.
Hepatology
70
,
1457
1469
[PubMed]
166.
Mueller
N.T.
,
Liu
T.
,
Mitchel
E.B.
,
Yates
K.P.
,
Suzuki
A.
,
Behling
C.
et al.
(
2020
)
Sex hormone relations to histologic severity of pediatric nonalcoholic fatty liver disease
.
J. Clin. Endocrinol. Metab.
105
,
3496
3504
[PubMed]
167.
Kuhl
J.
,
Hilding
A.
,
Ostenson
C.G.
,
Grill
V.
,
Efendic
S.
and
Bavenholm
P.
(
2005
)
Characterisation of subjects with early abnormalities of glucose tolerance in the Stockholm Diabetes Prevention Programme: the impact of sex and type 2 diabetes heredity
.
Diabetologia
48
,
35
40
[PubMed]
168.
Clausen
J.O.
,
Borch-Johnsen
K.
,
Ibsen
H.
,
Bergman
R.N.
,
Hougaard
P.
,
Winther
K.
et al.
(
1996
)
Insulin sensitivity index, acute insulin response, and glucose effectiveness in a population-based sample of 380 young healthy Caucasians. Analysis of the impact of gender, body fat, physical fitness, and life-style factors
.
J. Clin. Invest.
98
,
1195
1209
[PubMed]
169.
Klimek
P.
,
Kautzky-Willer
A.
,
Chmiel
A.
,
Schiller-Fruhwirth
I.
and
Thurner
S.
(
2015
)
Quantification of diabetes comorbidity risks across life using nation-wide big claims data
.
PLoS Comput. Biol.
11
,
e1004125
[PubMed]
170.
Wiik
A.
,
Gustafsson
T.
,
Esbjörnsson
M.
,
Johansson
O.
,
Ekman
M.
,
Sundberg
C.
et al.
(
2005
)
Expression of oestrogen receptor α and β is higher in skeletal muscle of highly endurance‐trained than of moderately active men
.
Acta Physiol. Scand.
184
,
105
112
[PubMed]
171.
Lundsgaard
A.M.
and
Kiens
B.
(
2014
)
Gender differences in skeletal muscle substrate metabolism - molecular mechanisms and insulin sensitivity
.
Front Endocrinol. (Lausanne)
5
,
195
[PubMed]
172.
Yao
Y.
,
Li
H.
,
Gu
Y.
,
Davidson
N.E.
and
Zhou
Q.
(
2010
)
Inhibition of SIRT1 deacetylase suppresses estrogen receptor signaling
.
Carcinogenesis
31
,
382
387
[PubMed]
173.
Tao
Z.
(
2019
)
Estrogen signaling interacts with Sirt1 in adipocyte autophagy
,
Virginia Tech
,
174.
Krause
W.C.
,
Rodriguez
R.
,
Gegenhuber
B.
,
Matharu
N.
,
Rodriguez
A.N.
,
Padilla-Roger
A.M.
et al.
(
2021
)
Oestrogen engages brain MC4R signalling to drive physical activity in female mice
.
Nature
599
,
131
135
[PubMed]
175.
Zhang
J.
(
2007
)
The direct involvement of SirT1 in insulin-induced insulin receptor substrate-2 tyrosine phosphorylation
.
J. Biol. Chem.
282
,
34356
34364
[PubMed]
176.
Li
Y.
,
Xu
W.
,
McBurney
M.W.
and
Longo
V.D.
(
2008
)
SirT1 inhibition reduces IGF-I/IRS-2/Ras/ERK1/2 signaling and protects neurons
.
Cell Metab.
8
,
38
48
[PubMed]
177.
Wang
R.H.
,
Kim
H.S.
,
Xiao
C.
,
Xu
X.
,
Gavrilova
O.
and
Deng
C.X.
(
2011
)
Hepatic Sirt1 deficiency in mice impairs mTorc2/Akt signaling and results in hyperglycemia, oxidative damage, and insulin resistance
.
J. Clin. Invest.
121
,
4477
4490
[PubMed]
178.
Matsumoto
M.
,
Pocai
A.
,
Rossetti
L.
,
Depinho
R.A.
and
Accili
D.
(
2007
)
Impaired regulation of hepatic glucose production in mice lacking the forkhead transcription factor Foxo1 in liver
.
Cell Metab.
6
,
208
216
[PubMed]
179.
Sundaresan
N.R.
,
Pillai
V.B.
,
Wolfgeher
D.
,
Samant
S.
,
Vasudevan
P.
,
Parekh
V.
et al.
(
2011
)
The deacetylase SIRT1 promotes membrane localization and activation of Akt and PDK1 during tumorigenesis and cardiac hypertrophy
.
Sci. Signal.
4
,
ra46
[PubMed]
180.
Nogueira
V.
,
Park
Y.
,
Chen
C.C.
,
Xu
P.Z.
,
Chen
M.L.
,
Tonic
I.
et al.
(
2008
)
Akt determines replicative senescence and oxidative or oncogenic premature senescence and sensitizes cells to oxidative apoptosis
.
Cancer Cell.
14
,
458
470
[PubMed]
181.
Chen
C.C.
,
Jeon
S.M.
,
Bhaskar
P.T.
,
Nogueira
V.
,
Sundararajan
D.
,
Tonic
I.
et al.
(
2010
)
FoxOs inhibit mTORC1 and activate Akt by inducing the expression of Sestrin3 and Rictor
.
Dev. Cell.
18
,
592
604
[PubMed]
182.
Segales
J.
,
Perdiguero
E.
,
Serrano
A.L.
,
Sousa-Victor
P.
,
Ortet
L.
,
Jardi
M.
et al.
(
2020
)
Sestrin prevents atrophy of disused and aging muscles by integrating anabolic and catabolic signals
.
Nat. Commun.
11
,
189
[PubMed]
183.
Cheng
Z.
(
2019
)
The FoxO-autophagy axis in health and disease
.
Trends Endocrinol. Metab.
30
,
658
671
[PubMed]
184.
Lee
J.H.
,
Budanov
A.V.
and
Karin
M.
(
2013
)
Sestrins orchestrate cellular metabolism to attenuate aging
.
Cell Metab.
18
,
792
801
[PubMed]
185.
Hevener
A.L.
,
Zhou
Z.
,
Moore
T.M.
,
Drew
B.G.
and
Ribas
V.
(
2018
)
The impact of ERα action on muscle metabolism and insulin sensitivity-Strong enough for a man, made for a woman
.
Mol. Metab.
15
,
20
34
[PubMed]
186.
Allard
C.
,
Morford
J.J.
,
Xu
B.
,
Salwen
B.
,
Xu
W.
,
Desmoulins
L.
et al.
(
2019
)
Loss of nuclear and membrane estrogen receptor-alpha differentially impairs insulin secretion and action in male and female mice
.
Diabetes
68
,
490
501
[PubMed]
187.
Kawakami
M.
,
Yokota-Nakagi
N.
,
Uji
M.
,
Yoshida
K.I.
,
Tazumi
S.
,
Takamata
A.
et al.
(
2018
)
Estrogen replacement enhances insulin-induced AS160 activation and improves insulin sensitivity in ovariectomized rats
.
Am. J. Physiol. Endocrinol. Metab.
315
,
E1296
E1304
[PubMed]
188.
Sano
H.
,
Kane
S.
,
Sano
E.
,
Miinea
C.P.
,
Asara
J.M.
,
Lane
W.S.
et al.
(
2003
)
Insulin-stimulated phosphorylation of a Rab GTPase-activating protein regulates GLUT4 translocation
.
J. Biol. Chem.
278
,
14599
14602
[PubMed]
189.
Park
Y.M.
,
Keller
A.C.
,
Runchey
S.S.
,
Miller
B.F.
,
Kohrt
W.M.
,
Van Pelt
R.E.
et al.
(
2019
)
Acute estradiol treatment reduces skeletal muscle protein breakdown markers in early- but not late-postmenopausal women
.
Steroids
146
,
43
49
[PubMed]
190.
Munoz-Mayorga
D.
,
Guerra-Araiza
C.
,
Torner
L.
and
Morales
T.
(
2018
)
Tau phosphorylation in female neurodegeneration: role of estrogens, progesterone, and prolactin
.
Front Endocrinol. (Lausanne)
9
,
133
[PubMed]
191.
Fatima
L.A.
,
Campello
R.S.
,
Barreto-Andrade
J.N.
,
Passarelli
M.
,
Santos
R.S.
,
Clegg
D.J.
et al.
(
2019
)
Estradiol stimulates adipogenesis and Slc2a4/GLUT4 expression via ESR1-mediated activation of CEBPA
.
Mol. Cell. Endocrinol.
498
,
110447
[PubMed]
192.
Gregorio
K.C.R.
,
Laurindo
C.P.
and
Machado
U.F.
(
2021
)
Estrogen and glycemic homeostasis: the fundamental role of nuclear estrogen receptors ESR1/ESR2 in glucose transporter GLUT4 regulation
.
Cells
10
,
99
[PubMed]
193.
Xu
B.
,
Allard
C.
,
Alvarez-Mercado
A.I.
,
Fuselier
T.
,
Kim
J.H.
,
Coons
L.A.
et al.
(
2018
)
Estrogens promote misfolded proinsulin degradation to protect insulin production and delay diabetes
.
Cell Rep.
24
,
181
196
[PubMed]
194.
Sachs
S.
,
Bastidas-Ponce
A.
,
Tritschler
S.
,
Bakhti
M.
,
Böttcher
A.
,
Sánchez-Garrido
M.A.
et al.
(
2020
)
Targeted pharmacological therapy restores β-cell function for diabetes remission
.
Nat. Metab.
2
,
192
209
[PubMed]
This is an open access article published by Portland Press Limited on behalf of the Biochemical Society and distributed under the Creative Commons Attribution License 4.0 (CC BY). Open access for this article was enabled by the participation of University of Florida in an all-inclusive Read & Publish agreement with Portland Press and the Biochemical Society under a transformative agreement with Individual.