The role of hypothalamic estrogen receptors in metabolic regulation

“First described in 1994 (Zhang et al., 1994), leptin has proven to be a key metabolic protein with actions throughout the body.”

“While mainly synthesized by the stomach, ghrelin is also found in the hypothalamus and several other brain areas [143; 144; 145].”

“NPY increases following OVX with concomitant reduction of E2, and administration of E2 to the ARC reverses this increase [84; 127].”

“The ”classical“ nuclear ER was cloned in 1985 [24] and renamed estrogen receptor alpha (ERα/ESR1) when a second nuclear estrogen receptor (estrogen receptor beta (ERβ/ESR2)), was discovered 10 years later [25].”

“Peripheral or CNS-delivered ghrelin increased feeding in intact male and OVX females rats [147; 148; 149; 150; 151; 152; 153]; however, the same hyperphagic levels were not achieved when administered to the intact/proestrus phase females [146].”

“Secreted from adipose tissues in direct proportion to adiposity, leptin crosses the blood-brain barrier and interacts with leptin receptors in the hypothalamus and brainstem to influence food intake and energy expenditure [14; 16; 60; 61; 62; 63; 64; 65; 66; 67; 68].”

“Peripheral or CNS-delivered ghrelin increased feeding in intact male and OVX females rats [147; 148; 149; 150; 151; 152; 153]; however, the same hyperphagic levels were not achieved when administered to the intact/proestrus phase females [146].”

“Secreted from adipose tissues in direct proportion to adiposity, leptin crosses the blood-brain barrier and interacts with leptin receptors in the hypothalamus and brainstem to influence food intake and energy expenditure [14; 16; 60; 61; 62; 63; 64; 65; 66; 67; 68].”

“While mainly synthesized by the stomach, ghrelin is also found in the hypothalamus and several other brain areas [143; 144; 145].”

“Peripheral or CNS-delivered ghrelin increased feeding in intact male and OVX females rats [147; 148; 149; 150; 151; 152; 153]; however, the same hyperphagic levels were not achieved when administered to the intact/proestrus phase females [146].”

“The ”classical“ nuclear ER was cloned in 1985 [24] and renamed estrogen receptor alpha (ERα/ESR1) when a second nuclear estrogen receptor (estrogen receptor beta (ERβ/ESR2)), was discovered 10 years later [25].”

“There are several splice variants of the leptin receptor: the long form (leprb) is thought to be critical for regulating energy balance [71].”

“ESR1 is expressed in several different brain regions implicated in regulating energy homeostasis, including the ventrolateral portion of the VMH (VL VMH), the arcuate nucleus (ARC), the medial preoptic area (MPOA), and the paraventricular nuclei (PVN) [26; 27; 28; 29; 30; 52; 53].”

“While mainly synthesized by the stomach, ghrelin is also found in the hypothalamus and several other brain areas [143; 144; 145].”

“He coined this the ‘adiposity theory of body weight regulation’ [91].”

“intake and energy expenditure (Zhang et al., 2008; Grill and Kaplan, 2002; Williams et al., 2001; Xu et al., 2011).”

“In addition, Mch is upregulated by fasting [158], and MCH neurons in the lateral hypothalamic area (LHA) receive inputs from NPY/ AgRP neurons in the ARC [16; 63; 161; 162; 163; 164].”

“ESR1 mediates the anti-obesity effects of estrogens; deletion of the receptor increases adiposity and causes the metabolic syndrome in both male and female mice (Heine et al., 2000).”

“Peripheral or CNS-delivered ghrelin increased feeding in intact male and OVX females rats [147; 148; 149; 150; 151; 152; 153]; however, the same hyperphagic levels were not achieved when administered to the intact/proestrus phase females [146].”

“The hypothalamus exerts its influence on energy homeostasis through regulation of both anabolic and catabolic pathways [16; 17; 18].”

“Consequently, within the ARC, leptin/insulin elicits a powerful catabolic affect by activating αMSH and simultaneously inhibiting anabolic NPY/AgRP release [14].”

“Central administration of MCH promotes feeding [157; 158], while genetic ablation of the Mch gene produces a lean phenotype [159; 160].”

“Once thought to function solely as genomic transcription factors [34; 35]; however, ERs have also been shown to participate in non-genomic signaling pathways.”

“Lesions of the ventral medial hypothalamus (VMH) increased food intake and induced obesity [6; 7].”

“Specifically, leptin provides a powerful catabolic signal to the brain, inhibiting food intake and increasing energy expenditure [14; 16; 60; 61; 62; 63; 64; 65; 66; 67; 69; 70].”

“NPY increases following OVX with concomitant reduction of E2, and administration of E2 to the ARC reverses this increase [84; 127].”

“Secreted from adipose tissues in direct proportion to adiposity, leptin crosses the blood-brain barrier and interacts with leptin receptors in the hypothalamus and brainstem to influence food intake and energy expenditure [14; 16; 60; 61; 62; 63; 64; 65; 66; 67; 68].”

“Collectively, these findings suggest that ESR1 functions in POMC neurons to influence energy homeostasis and may provide a mechanism for the anorexigenic effects of E2.”

“Subsequently, it has been shown that insulin is not secreted by the adipose tissues per se, but is secreted relative to overall adipose tissue mass [92; 93; 94; 95; 96].”

“Thus, the Dual-Center Hypothesis became the dominant theory of how the central nervous system (CNS) controls food intake (Stellar, 1954; Elmquist et al., 1999; Jeanrenaud and Rohner-Jeanrenaud, 2000).”

“Obese animals and humans have higher basal insulin levels and secrete more insulin in response to a meal than lean individuals [94; 97].”

“Additionally, female Ghsr−/− mice were leaner than males, and accumulated less body weight and adiposity following exposure to an obesigenic high-fat diet [154].”

“Extra nuclear and membrane-associated isoforms of ESR1 and ESR2 localize to plasma membrane caveolae and congregate with signaling molecules, including G proteins, growth factor receptors, tyrosine kinases (Src), linker proteins (MNAR), and orphan GPCRs, facilitating interaction and rapid intracellular signaling in th…”

“expenditure, as well as increased visceral adiposity in the perigonadal depot (Xu et al., 2011).”

“Central administration of NPY potently increases food intake and decreases energy expenditure and fat oxidation [107; 108; 109; 110].”

“The arcuate nucleus (ARC) has been demonstrated to be a key site of leptin and insulin receptor activation and activity [3; 68].”

“Peripheral or CNS-delivered ghrelin increased feeding in intact male and OVX females rats [147; 148; 149; 150; 151; 152; 153]; however, the same hyperphagic levels were not achieved when administered to the intact/proestrus phase females [146].”

“Critically, OVX or removal of endogenous estrogens has been shown to decrease sensitivity to leptin delivered to the brain, while E2 replacement following OVX restored the anorexigenic effects of leptin [23].”

“Once thought to function solely as genomic transcription factors [34; 35]; however, ERs have also been shown to participate in non-genomic signaling pathways.”

“Consequently, within the ARC, leptin/insulin elicits a powerful catabolic affect by activating αMSH and simultaneously inhibiting anabolic NPY/AgRP release [14].”

“Leptin has the ability to activate or inhibit hypothalamic neurons [73; 75; 76].”

“Subsequently, we have reported that site-specific reductions of ESR1 in the VL VMH using a small hairpin (sh) interference RNA decreased sensitivity to E2-induced weight loss, as well as decreased energy expenditure and increased visceral fat deposition, implicating VL VMH ESR1 in energy homeostasis [58].”

“Additionally, insulin receptors are distributed in discrete brain areas, including the hypothalamus [98; 99; 100], and activation of hypothalamic insulin receptors decreases food intake and body weight [16; 62; 101; 102; 103].”

“Leptin levels are higher in females, even before puberty, when compared with males, and these levels are independent of differences in body composition [80; 81; 82].”

“E2 activates POMC neurons partly via PI3K-mediated mechanisms [123; 124].”

“Subsequently, it has been shown that insulin is not secreted by the adipose tissues per se, but is secreted relative to overall adipose tissue mass [92; 93; 94; 95; 96].”

“Leprb“s are localized in several brain areas including the VMH and the ARC, and are co-localized with several other receptors and neuronal pathways believed to be involved in controlling food intake, energy homeostasis and reproduction [72; 73; 74].”

“Collectively, these findings suggest that ESR1 functions in POMC neurons to influence energy homeostasis and may provide a mechanism for the anorexigenic effects of E2.”

“Additionally, insulin receptors are distributed in discrete brain areas, including the hypothalamus [98; 99; 100], and activation of hypothalamic insulin receptors decreases food intake and body weight [16; 62; 101; 102; 103].”

“Additionally, insulin receptors are distributed in discrete brain areas, including the hypothalamus [98; 99; 100], and activation of hypothalamic insulin receptors decreases food intake and body weight [16; 62; 101; 102; 103].”

“These synaptic rearrangements in POMC neurons tightly parallel the effects of E2 on food intake, energy expenditure and body weight [125].”

“Additionally, insulin receptors are distributed in discrete brain areas, including the hypothalamus [98; 99; 100], and activation of hypothalamic insulin receptors decreases food intake and body weight [16; 62; 101; 102; 103].”

“Electrical stimulation of the two hypothalamic centers supported the hypothesis: stimulation of the VMH caused rats to stop eating [12], while stimulation of the LHA caused sated rats to eat [13].”

“Within the brain, the hypothalamus is a complex structure of nuclei, pathways and neurotransmitter systems that controls food intake and energy expenditure [1; 2; 3; 4].”

“nucleus (ARC), the medial preoptic area (MPOA), and the paraventricular nuclei (PVN) (Osterlund et al., 1998; Merchenthaler et al., 2004; Simonian and Herbison, 1997; Voisin et al., 1997; Simerly et al., 1990; Shima et al., 2003; Wilkinson et al., 2002).”

“Leptin has the ability to activate or inhibit hypothalamic neurons [73; 75; 76].”

“Green S, Walter P, Kumar V, Krust A, Bornert JM, Argos P, Chambon P. Human oestrogen receptor cDNA: sequence, expression and homology to v-erb-A.”

“ERs also activate protein kinase B (PKB/Akt) in neurons [42; 43; 44], and activation of the PI3K/Akt cascade mediates a variety of E2“s central actions, including neuronal excitability, neuro-protection, reductions in inflammation, and neurite outgrowth [45], as well as body weight regulation.”

“Both leptin and insulin administration decrease NPY/AgRP mRNA, demonstrating leptin/insulin are critical determinants of ARC NPY activity [106].”

“nucleus (ARC), the medial preoptic area (MPOA), and the paraventricular nuclei (PVN) (Osterlund et al., 1998; Merchenthaler et al., 2004; Simonian and Herbison, 1997; Voisin et al., 1997; Simerly et al., 1990; Shima et al., 2003; Wilkinson et al., 2002).”

“Subsequently, it has been shown that insulin is not secreted by the adipose tissues per se, but is secreted relative to overall adipose tissue mass [92; 93; 94; 95; 96].”

“Additionally, insulin receptors are distributed in discrete brain areas, including the hypothalamus [98; 99; 100], and activation of hypothalamic insulin receptors decreases food intake and body weight [16; 62; 101; 102; 103].”

“Higher levels of estrogens have been associated with increased leptin sensitivity [84; 85; 86]; however, some studies have failed to observe direct estrogen-leptin interactions [87; 88; 89].”

“less effective in this regard; its deletion does not promote obesity or any of the metabolic consequences associated with obesity (Ohlsson et al., 2000).”

“Specifically, leptin provides a powerful catabolic signal to the brain, inhibiting food intake and increasing energy expenditure [14; 16; 60; 61; 62; 63; 64; 65; 66; 67; 69; 70].”

“Lesions of the ventral medial hypothalamus (VMH) increased food intake and induced obesity [6; 7].”

“E2 may affect the expression of MCH-1 receptors [26; 169], an idea supported by work demonstrating LHA neurons containing MCH-1 receptors have ERs in close proximity [170].”

“Early attempts to determine the influence of E2 and their receptors in regulating food intake and body weight in the CNS were performed by intra-nuclear microinjections of estradiol benzoate (E2) [54].”

“Peripheral or CNS-delivered ghrelin increased feeding in intact male and OVX females rats [147; 148; 149; 150; 151; 152; 153]; however, the same hyperphagic levels were not achieved when administered to the intact/proestrus phase females [146].”

“Secreted from adipose tissues in direct proportion to adiposity, leptin crosses the blood-brain barrier and interacts with leptin receptors in the hypothalamus and brainstem to influence food intake and energy expenditure [14; 16; 60; 61; 62; 63; 64; 65; 66; 67; 68].”

“Higher levels of estrogens have been associated with increased leptin sensitivity [84; 85; 86]; however, some studies have failed to observe direct estrogen-leptin interactions [87; 88; 89].”

“GPER also induces the expression of ERS136, a transcriptionally inactive and truncated version of the classical long isoform of ERS1, ERS166 [48]; however, its function with respect to metabolism remains unclear.”

“Peripheral or CNS-delivered ghrelin increased feeding in intact male and OVX females rats [147; 148; 149; 150; 151; 152; 153]; however, the same hyperphagic levels were not achieved when administered to the intact/proestrus phase females [146].”

“Secreted from adipose tissues in direct proportion to adiposity, leptin crosses the blood-brain barrier and interacts with leptin receptors in the hypothalamus and brainstem to influence food intake and energy expenditure [14; 16; 60; 61; 62; 63; 64; 65; 66; 67; 68].”

“The arcuate nucleus (ARC) has been demonstrated to be a key site of leptin and insulin receptor activation and activity [3; 68].”

“CCK slows gastric emptying and intestinal motility [129], as well as increases satiation by activating subdiaphragmatic vagal afferent neurons [130; 131].”

“Chronic administration of aMSH reduces body weight and adiposity (Pierroz et al., 2002).”

“MCH is an orexigenic hormone and important regulator of energy homeostasis [156].”

“Interestingly, while highly active estrogens such as 17 beta-estradiol (E2) function as ER ligands, many pharmacological, as well as environmental and food compounds, are capable of binding and promoting ER activity [36].”

“ERs also activate protein kinase B (PKB/Akt) in neurons [42; 43; 44], and activation of the PI3K/Akt cascade mediates a variety of E2“s central actions, including neuronal excitability, neuro-protection, reductions in inflammation, and neurite outgrowth [45], as well as body weight regulation.”

“Obese animals and humans have higher basal insulin levels and secrete more insulin in response to a meal than lean individuals [94; 97].”

“CCK satiation relies on vagal afferents [137; 138; 139], and upregulation of CCK receptors in terminals of vagal afferent fibers increases CCK sensitivity.”

“Evidence for this comes from in vitro quantitative autoradiography which measured the effects of E2 on the binding characteristics of CCK receptors in the nucleus of the solitary tract (NTS), a brain area that receives terminal projections of abdominal vagal afferent fibers [137], as well as in two interconnected area…”

“Leprb“s are localized in several brain areas including the VMH and the ARC, and are co-localized with several other receptors and neuronal pathways believed to be involved in controlling food intake, energy homeostasis and reproduction [72; 73; 74].”

“Importantly, with respect to estrogenic regulation of these neuronal populations in the ARC, ESR1 is not co-localized or expressed on NPY/AgRP neurons [115]; however, we and others have found POMC neurons do express ESR1 [4; 116; 117].”

“CCK slows gastric emptying and intestinal motility [129], as well as increases satiation by activating subdiaphragmatic vagal afferent neurons [130; 131].”

“In one study of female mice lacking GPER, the obesity phenotype emerged in only one of four GPER mutant mouse lines [46; 47].”

“Secreted from adipose tissues in direct proportion to adiposity, leptin crosses the blood-brain barrier and interacts with leptin receptors in the hypothalamus and brainstem to influence food intake and energy expenditure [14; 16; 60; 61; 62; 63; 64; 65; 66; 67; 68].”

“Other evidence suggests E2 increases the sensitivity of vagal CCK-A receptors [140; 141; 142], providing another plausible explanation for the anorexigenic effect of E2.”

“ESR1 is expressed in several different brain regions implicated in regulating energy homeostasis, including the ventrolateral portion of the VMH (VL VMH), the arcuate nucleus (ARC), the medial preoptic area (MPOA), and the paraventricular nuclei (PVN) [26; 27; 28; 29; 30; 52; 53].”

“Surprisingly, despite thousands of reports published since the 1930“s investigating the role of various hypothalamic nuclei in the regulation of food intake and body weight [19; 20; 21], studies of the effect of sex on the hormonal and neuronal pathways of energy regulation have been sparse.”

“Central administration of NPY potently increases food intake and decreases energy expenditure and fat oxidation [107; 108; 109; 110].”

“For example, the E2/ER complex induces activation of the mitogen-activated protein (MAP) kinase cascade and phosphatidylinositol 3-kinase (PI3K) pathways, causing a rise in intracellular calcium [40; 41].”

“ESR1 is expressed in several different brain regions implicated in regulating energy homeostasis, including the ventrolateral portion of the VMH (VL VMH), the arcuate nucleus (ARC), the medial preoptic area (MPOA), and the paraventricular nuclei (PVN) [26; 27; 28; 29; 30; 52; 53].”

“The ARC and VMH are two hypothalamic nuclei that are relatively small structures/areas which are difficult to selectively target; therefore, earlier microinjection studies were not able to rigorously distinguish these two regions and failed to provide consistent results [55].”

“nucleus (ARC), the medial preoptic area (MPOA), and the paraventricular nuclei (PVN) (Osterlund et al., 1998; Merchenthaler et al., 2004; Simonian and Herbison, 1997; Voisin et al., 1997; Simerly et al., 1990; Shima et al., 2003; Wilkinson et al., 2002).”

“Central administration of MCH promotes feeding [157; 158], while genetic ablation of the Mch gene produces a lean phenotype [159; 160].”

“Leptin levels are higher in females, even before puberty, when compared with males, and these levels are independent of differences in body composition [80; 81; 82].”

“CCK antagonists increase food intake by increasing meal size [132].”

“Higher levels of estrogens have been associated with increased leptin sensitivity [84; 85; 86]; however, some studies have failed to observe direct estrogen-leptin interactions [87; 88; 89].”

“Leptin treatment in pregnant rats impaired activation of pSTAT3 and reduced leprb mRNA in the VMH when compared to non-pregnant females [90].”

“For example, while NPY promotes food intake and body weight gain [110], E2 suppresses NPY release.”

“ERs also activate protein kinase B (PKB/Akt) in neurons [42; 43; 44], and activation of the PI3K/Akt cascade mediates a variety of E2“s central actions, including neuronal excitability, neuro-protection, reductions in inflammation, and neurite outgrowth [45], as well as body weight regulation.”

“CCK-A antagonists decreased food intake to a greater extent in E2-treated OVX mice and intact females in proestrus, and this effect was lessened in rats with low E2 levels [133; 134; 135; 136].”

“The physiologic responses mediated by ERs vary across cells and depend upon the presence and concentration of ER subtypes, ligands, and co-activator and co-repressor proteins (McDonnell and Wardell, 2010; Powell and Xu, 2008).”

“For example, the E2/ER complex induces activation of the mitogen-activated protein (MAP) kinase cascade and phosphatidylinositol 3-kinase (PI3K) pathways, causing a rise in intracellular calcium [40; 41].”

“In one study of female mice lacking GPER, the obesity phenotype emerged in only one of four GPER mutant mouse lines [46; 47].”

“OVX with concomitant reductions in circultating E2 decreases POMC mRNA, an effect reversed by E2 replacement [121].”

“CCK-A antagonists decreased food intake to a greater extent in E2-treated OVX mice and intact females in proestrus, and this effect was lessened in rats with low E2 levels [133; 134; 135; 136].”

“ESR1 is expressed in several different brain regions implicated in regulating energy homeostasis, including the ventrolateral portion of the VMH (VL VMH), the arcuate nucleus (ARC), the medial preoptic area (MPOA), and the paraventricular nuclei (PVN) [26; 27; 28; 29; 30; 52; 53].”

“The ER subtypes are expressed differentially throughout the brain [25; 26; 27; 28; 29; 30; 31; 32; 33], and in many cases their distribution differs by sex.”

“It was hypothesized the lesions affected satiety, leading the VMH to be dubbed the ”satiety center“ [8; 9].”

“ESR1 is expressed in several different brain regions implicated in regulating energy homeostasis, including the ventrolateral portion of the VMH (VL VMH), the arcuate nucleus (ARC), the medial preoptic area (MPOA), and the paraventricular nuclei (PVN) [26; 27; 28; 29; 30; 52; 53].”

“Extra nuclear and membrane-associated isoforms of ESR1 and ESR2 localize to plasma membrane caveolae and congregate with signaling molecules, including G proteins, growth factor receptors, tyrosine kinases (Src), linker proteins (MNAR), and orphan GPCRs, facilitating interaction and rapid intracellular signaling in th…”

“ERs also activate protein kinase B (PKB/Akt) in neurons [42; 43; 44], and activation of the PI3K/Akt cascade mediates a variety of E2“s central actions, including neuronal excitability, neuro-protection, reductions in inflammation, and neurite outgrowth [45], as well as body weight regulation.”

“Consequently, within the ARC, leptin/insulin elicits a powerful catabolic affect by activating αMSH and simultaneously inhibiting anabolic NPY/AgRP release [14].”

“E2 activates POMC neurons partly via PI3K-mediated mechanisms [123; 124].”

“CCK-A antagonists decreased food intake to a greater extent in E2-treated OVX mice and intact females in proestrus, and this effect was lessened in rats with low E2 levels [133; 134; 135; 136].”

“Other evidence suggests E2 increases the sensitivity of vagal CCK-A receptors [140; 141; 142], providing another plausible explanation for the anorexigenic effect of E2.”

“Higher levels of estrogens have been associated with increased leptin sensitivity [84; 85; 86]; however, some studies have failed to observe direct estrogen-leptin interactions [87; 88; 89].”

“Electrical stimulation of the two hypothalamic centers supported the hypothesis: stimulation of the VMH caused rats to stop eating [12], while stimulation of the LHA caused sated rats to eat [13].”

“(Messina et al., 2006).”

“CCK satiation relies on vagal afferents [137; 138; 139], and upregulation of CCK receptors in terminals of vagal afferent fibers increases CCK sensitivity.”

“NPY increases following OVX with concomitant reduction of E2, and administration of E2 to the ARC reverses this increase [84; 127].”

“Effects of E2 in the MPOA have also been controversial, with only one report showing an anorexigenic response following sight-directed E2 administration [57], whereas several others have demonstrated E2 implanted in this nucleus has no effect on feeding [55].”

“In support of this hypothesis, physiological doses of E2 decreased pre-pro MCH mRNA expression in the ZI of OVX rats [166] and the LHA of obese male rats [167].”

“Peripheral or CNS-delivered ghrelin increased feeding in intact male and OVX females rats [147; 148; 149; 150; 151; 152; 153]; however, the same hyperphagic levels were not achieved when administered to the intact/proestrus phase females [146].”

“CCK slows gastric emptying and intestinal motility [129], as well as increases satiation by activating subdiaphragmatic vagal afferent neurons [130; 131].”

“Thus, the Dual-Center Hypothesis became the dominant theory of how the central nervous system (CNS) controls food intake [5; 14; 15].”

“In contrast, pharmacological doses of E2 in male mice increased MCH mRNA within hypothalamic tissue punches [168].”

“In addition, chronic E2 treatment in male rats blocked increases in LH MCH mRNA expression induced by fasting [167].”

“NPY increases following OVX with concomitant reduction of E2, and administration of E2 to the ARC reverses this increase [84; 127].”

“Leptin levels are higher in females, even before puberty, when compared with males, and these levels are independent of differences in body composition [80; 81; 82].”

“Extra nuclear and membrane-associated isoforms of ESR1 and ESR2 localize to plasma membrane caveolae and congregate with signaling molecules, including G proteins, growth factor receptors, tyrosine kinases (Src), linker proteins (MNAR), and orphan GPCRs, facilitating interaction and rapid intracellular signaling in th…”

“Importantly with respect to the potential role of estrogens to regulate energy homeostasis, leprb expression in the ARC is co-localized with ESR1 [77], and estrogens have been reported to regulate the expression of leprb in the ARC [78], possibly via an ERE on the leptin receptor gene [79].”

“However, subsequent studies failed to reproduce these phenotypes in rats with PVN implants of E2 [56].”

“Lower POMC levels are also observed in ESR1 knockout mice [122].”

“It was hypothesized the lesions affected satiety, leading the VMH to be dubbed the ”satiety center“ [8; 9].”

“Surprisingly, despite thousands of reports published since the 1930“s investigating the role of various hypothalamic nuclei in the regulation of food intake and body weight [19; 20; 21], studies of the effect of sex on the hormonal and neuronal pathways of energy regulation have been sparse.”

“nucleus (ARC), the medial preoptic area (MPOA), and the paraventricular nuclei (PVN) (Osterlund et al., 1998; Merchenthaler et al., 2004; Simonian and Herbison, 1997; Voisin et al., 1997; Simerly et al., 1990; Shima et al., 2003; Wilkinson et al., 2002).”

“Additionally, insulin receptors are distributed in discrete brain areas, including the hypothalamus [98; 99; 100], and activation of hypothalamic insulin receptors decreases food intake and body weight [16; 62; 101; 102; 103].”

“Extra nuclear and membrane-associated isoforms of ESR1 and ESR2 localize to plasma membrane caveolae and congregate with signaling molecules, including G proteins, growth factor receptors, tyrosine kinases (Src), linker proteins (MNAR), and orphan GPCRs, facilitating interaction and rapid intracellular signaling in th…”

“Hart-Unger and Korach summarized these findings [126], indicating that E2 acts on hypothalamic POMC neurons to suppress food intake and maintain the negative feedback loop.”

“In contrast, lesions of the lateral hypothalamic area (LHA) decreased food intake and provoked weight loss [10]; this region became known as the ”hunger center“ [11].”

“Much of our understanding on the molecular pathways that ER action regulates cardiovascular health and metabolism has been derived exclusively from rodent models (33).”

“It has been demonstrated that estrogens potentiate leptin action by increasing the expression and sensitivity of its receptors in the hypothalamus [16].”

“The expression of estrogen receptors in several hypothalamic nuclei fluctuate throughout the estrous cycle possibly altering its intrinsic activity (Acevedo-Rodriguez et al., 2015; Brown et al., 1992; Frank et al., 2014).”

“To further support a role for GLP-1R signaling in regulating food reward, recent fMRI studies in obese and obese T2DM patients have demonstrated that intravenous infusion of exenatide decreases the activation of brain regions involved in mediating food reward (van Bloemendaal et al., 2014).”

“sensitivity as well as prevention of lipid accumulation and inflammation [20,21,67,68].”

“Therefore, hypothalamic estrogen responsiveness of Magel2 and Irs4 may be related to estrogen effects on metabolism (37).”

“ERα is the main mediator of estrogen action in CNS and play important roles in maintaining function of specialized neuronal circuits such as pro-opiomelanocortin (POMC) neurons or ventral medial hypothalamus (VMH) and regulating levels and activity of several adipokines including leptin, adiponectin and NPY [82,83].”

“Receptor-selective pharmacological (28) and genetic manipulations (29-31) suggest a primary role for ERα in mediating the metabolic effects of estrogens on the hypothalamus, although other receptor(s) are clearly involved in the effects of estrogens on temperature.”

“Among all the ERs, ERα is considered to be the receptor primarily responsible for energy homeostatic modulation in the CNS and in the periphery [40, 49].”

“A sexual dimorphism in the role of hypothalamic ERα signaling also has been demonstrated in mice, as ERα silencing in the ventromedial nucleus of the hypothalamus led to body weight gain in female but not male mice (Frank et al. 2014).”

“cystokinin [CCK] and ghrelin), neurotransmitters, and adipocytes.(64) Estrogen mediates the release of the satiating CCK from the small intestine,(65) which acts to decrease meal sizes (rather than the frequency of eating)(66) and attenuates the release of the appetite-stimulating hormone, ghrelin.”

“In contrast, the role of ESR2 in energy homeostasis and metabolism has been highly controversial (13, 23, 27, 30, 47, 53, 56).”

“It is also estrogen-regulated [62], which may explain, in part, the established link between estrogen and body fat distribution [63].”

“Data have been provided indicating that estrogens induce and testosterone inhibits leptin synthesis, respectively [106].”

“…peptide-1 (GLP-1), and other hormones such as insulin and leptin, which stimulate the release of neurotransmitters responsible for the feeling of satiety and inhibit the release of neurotransmitters responsible for the feeling of hunger in the arcuate nucleus of the hypothalamus [26–29].”

“[8] Frank A, Brown LM, Clegg DJ.”

“The ventromedial hypothalamic nucleus (VMN) is a critical site of 17bE action in energy balance [2].”

“Prepubescent women already have higher leptin concentrations than men and this difference only increases after puberty as estrogen induces leptin synthesis and secretion, while testosterone reduces it [70].”

“In addition, E2 induces ERα recruitment to ERE sites in target genes of mouse uterus, which leads to RNA and DNA syntheses, epithelial cell proliferation, and their differentiation toward a columnar secretory epithelium [42].”

“Despite that E2 can modulate metabolism by directly acting on peripheral tissues, emerging evidence suggests that the hypothalamus mediates a large part of the actions of E2 on energy balance (100).”

“Given oestrogen’s influence on energy expenditure and feeding behaviour, ERs in the hypothalamus (the brain region responsible for coordination of energy balance) in particular have been studied extensively 117 .”

“It is not surprising that E2 treatment decreased adiposity, since estrogen is involved in leptin signaling and other regulators of metabolic homeostasis [45,46].”

“The effects of estrogen on energy balance are believed to occur through estrogen receptormediated signaling within the hypothalamus (Frank et al. 2014).”

“28 A follow-up study using ovariectomized and gonad-intact female mice and rats has been proved this phenomenon.”

“Estradiol also regulates the development of cells in the hypothalamus that generate GHRH, which subsequently control adult the male pulsatile GH signaling [51,58,60].”

“First, activation of the GH signaling pathway by STAT5 phosphorylation [22, 64, 73, 74] and second, activation of sex hormone pathways by decreasing AR [22, 75, 76] and enhancing ESR1 [22, 77, 78] and estradiol levels [22, 45, 79] that lead to feminized liver gene expression [22].”

“The hypothesized physiological reason for these variations is that E2 may inhibit appetite in the late follicular phase (47) via a complex process involving hypothalamic E2 neurons and their regulatory role in energy homeostasis (48).”

“Epigenetic changes under E2 control have an impact on memory consolidation and energy expenditure in hypothalamus (Zhao et al., 2010; Frick et al., 2011; Frank et al., 2014; Frontiers in Cellular Neuroscience | www.frontiersin.org 1 June 2016 | Volume 10 | Article 147 López and Tena-Sempere, 2015).”

“The pivotal roles of estrogen signaling in the metabolic network were thoroughly reviewed by several groups recently (Roepke, 2009; Barros and Gustafsson, 2011; Mauvais-Jarvis et al., 2013; Frank et al., 2014; Kim et al., 2014; Palmer and Clegg, 2015).”

“Hence, although it is generally accepted that timing of events is SCN dependent, it is also likely that peripheral oscillators expressing ERs may play a role in the timing and stabilization of clocks and metabolic rhythms in the brain and the periphery (Frank et al., 2014; Rando and Wahli, 2011; Yan and Silver, 2015).”

“E2 actions in hypothalamic nuclei differentially control food intake, energy expenditure, and white adipose tissue distribution [1–4].”

“Phytoestrogens, in particular genistein, which is able to interact with the estrogen-dependent neural pathways in complex and multidirectional ways [4,5], may interfere with the endocrine system, leading to permanent alterations of estrogen sensitive circuits [6].”

“While mRNA levels of Crh2, Prlhr, Prhr, Kiss1, Esr1, and Gabre were significantly down-regulated in ARC of MTHF dams compared to FA dams at parturition, mRNA levels of Gabra4, Gabrd, Drd2, Grm2 and Cck were significantly up-regulated in MTHF dams (Figure 4A, p 0.05) corroborating RNAseq results.”

“The impact of estrogen on body weight maintenance involves not only regulation of glucose homeostasis but also food consumption, energy expenditure, fat deposition, and hepatic gluconeogenesis and glycogenolysis (1, 10, 25).”

“Low levels of estrogen, occurring due to menopause, ovarian insufficiency, or ovariectomy (Ovx), are associated with decreased energy expenditure and increased food intake, likely leading to weight gain and obesity in the long term [6, 7].”

“Estrogens also regulate key aspects of metabolism, including food intake, body weight and insulin sensitivity [8].”

“Furthermore, knocking out the αER on POMC neurons leads to increased food consumption and body weight in female but not male mice [24].”

“Interestingly, the activation of 5-HT2CR was found to promote ER α synthesis in the hypothalamus, which may result in estrogen-induced obesity [64, 65].”

“For this study, punches from the mPOA, AHA, PVN, rostral ARC, and caudal ARC were studied.”

“The effect may be seen in changes in overall sympathetic activity during the menstrual cycle as there are oestrogen receptors in the hypothalamus (Frank et al., 2014) and other areas of the autonomic nervous system.”

“This complex network of glands (including the hypothalamus and peripheral organs such as the liver, pancreas, and adipose tissue) (Frank et al. 2014; Lopez and Tena-Sempere 2015; Mahboobifard et al. 2022) release specific hormones into the bloodstream.”

“Furthermore, knocking out the αER on POMC neurons leads to an increase in food consumption and body weight in female but not male mice [21].”

“Previous research has demonstrated that another factor playing a key role in regulating food consumption across the estrous cycle is negative postingestive feedback (Eckel, 2004).”