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).”

“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].”

“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].”

“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].”

“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…”

“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].”

“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].”

“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].”

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

“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].”

“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].”

“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).”

“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].”

“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].”

“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].”

“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].”

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

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

“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.”

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

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

“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].”

“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, 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.”

“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].”

“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].”

“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].”

“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…”

“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].”

“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].”