Sexual differences in the control of energy homeostasis

“It has been estimated that 47 million individuals in the United States have obesity-related metabolic diseases [53].”

“Leptin is secreted in direct proportion to body fat, entering the brain from the blood, and interacting with specific receptors on neurons in the hypothalamus and other areas [2], [145] and [171].”

“As previously mentioned, on average, women carry more fat subcutaneously [42], [66],[80], [89] and [90]; whereas men carry more fat viscerally [167].”

“Hence, there are sex-based differences with regard to obesity-associated health risks with obese men being more likely to develop secondary metabolic complications and cardiovascular diseases than obese women [36], [83], [87], [92] and [169].”

“Leptin is secreted at a higher rate from subcutaneous fat than from visceral fat [28] and [113], thus circulating leptin correlates better with total subcutaneous fat than with total body fat [30], [35], [42], [57], [76], [106], [126], [140] and [141].”

“In contrast, excess adiposity in the gluteal / femoral subcutaneous region (‘gynoid’ or female-pattern) is poorly correlated with risk for these metabolic disorders [18], [39], [40], [88] and [123].”

“Hence, there are sex-based differences with regard to obesity-associated health risks with obese men being more likely to develop secondary metabolic complications and cardiovascular diseases than obese women [36], [83], [87], [92] and [169].”

“However, most animals match caloric intake with caloric expenditure quite precisely, resulting in relatively stable fat stores [74] and [77].”

“Comparable phenomenon has been reported in a recent human study that men, but not women, lose body weight, body fat and waist circumference following intranasal insulin administration [65], an approach that increases insulin concentration of the cerebrospinal fluid and thereby alters brain functions [24].”

“When obese ob/ob mice are engineered to overexpress adiponectin in adipose tissue, there is a massive increase in subcutaneous fat, and this is associated with improved insulin sensitivity and decreased glucose and insulin levels, increased lipid clearance, improved diacylglycerol levels and fully functional healthy p…”

“[67] reported that male and female mice with a targeted deletion in the ERa subunit (aERKO) have increased adiposity, consistent with other evidence linking estrogen with body weight regulation and adipocyte function.”

“Body weight regulation is thought to occur through negative feedback mechanisms which characterize most homeostatic systems [43], [131], [144], [146] and [172] involving adiposity signals.”

“Excess adiposity in the central visceral region of the body (‘android’ or male-pattern obesity [167]) is correlated with increased risk and mortality from disorders including diabetes, hyperlipidemia, hypertension, and atherosclerosis [11], [56] and [73].”

“female—The increasing prevalence of obesity throughout the world [51], [122] and [127] is associated with an escalating incidence of obesity-related disorders and health costs [5].”

“Leptin is secreted at a higher rate from subcutaneous fat than from visceral fat [28] and [113], thus circulating leptin correlates better with total subcutaneous fat than with total body fat [30], [35], [42], [57], [76], [106], [126], [140] and [141].”

“[157], they found transplantation of subcutaneous adipose tissue into intra-abdominal adipose tissue improved metabolic parameters.”

“Leptin is secreted at a higher rate from subcutaneous fat than from visceral fat [28] and [113], thus circulating leptin correlates better with total subcutaneous fat than with total body fat [30], [35], [42], [57], [76], [106], [126], [140] and [141].”

“Intra-abdominal fat is relatively insensitive to insulin [23] and [104], and insulin action is markedly impaired in individuals with visceral obesity [26] and [121].”

“higher risk of developing adverse events later in life [55] and [116].”

“Surgical removal of intra-abdominal adipose tissue results in decreased insulin and glucose levels in humans [156]; improves glucose tolerance in male and female mice [150]; and prevents the onset of age-dependent insulin resistance and glucose intolerance in male rats [58].”

“Leptin levels are inversely correlated with testosterone [69], [82], [98], [160] and [162] and exposure of human fat cells to testosterone or dihydrotestosterone inhibits leptin expression [162].”

“Leptin is secreted at a higher rate from subcutaneous fat than from visceral fat [28] and [113], thus circulating leptin correlates better with total subcutaneous fat than with total body fat [30], [35], [42], [57], [76], [106], [126], [140] and [141].”

“Lipolysis correlates positively with activation of the sympathetic nervous system [4] which may further enhance free fatty acid release into portal circulation [95].”

“Additionally, subcutaneous adipose tissue, which accounts for a higher percentage of adipose tissue in females, secretes leptin, and the secreted leptin may activate CNS leptin receptors, and this may directly influence leptin-induced activation of the sympathetic nervous system.”

“Estrogen regulates adiposity—Visceral fat varies inversely with estrogen levels [12], [13], [15], [25] and [49].”

“ERα is necessary for estradiol’s genomic actions with respect to body weight regulation [118], whereas ERβ functions more as a modulator of estrogen actions [143].”

“In situations where there is a prolonged positive energy balance, adipocytes take up circulating fatty acids and leads to increases in both adipocyte size and number, which is manifested more generally as an increased body fat mass [50].”

“Intra-abdominal adipose tissue has adipogenic, metabolic, pro-atherogenic, and pro-thrombotic characteristics [86], [112] and [158].”

“Leptin is secreted at a higher rate from subcutaneous fat than from visceral fat [28] and [113], thus circulating leptin correlates better with total subcutaneous fat than with total body fat [30], [35], [42], [57], [76], [106], [126], [140] and [141].”

“This has been reviewed by Asarian and Geary [7].”

“Estrogen regulates adiposity—Visceral fat varies inversely with estrogen levels [12], [13], [15], [25] and [49].”

“Surgical removal of intra-abdominal adipose tissue results in decreased insulin and glucose levels in humans [156]; improves glucose tolerance in male and female mice [150]; and prevents the onset of age-dependent insulin resistance and glucose intolerance in male rats [58].”

“Consistent with numerous previous reports [22], [41], [75], [93], [163], [164],[165] and [168], OVX results in a rapid increase in food intake and body weight relative to sham operated females, and this behavioral response is abolished by estradiol treatment alone [6].”

“In contrast to what occurs in non-pregnant woman, lipolysis in the gluteal / femoral subcutaneous adipose tissue is significantly less, thereby supporting lipogenesis until early pregnancy [133].”

“body fat distribution in humans [59,63,64] and in rats [29].”

“[120].”

“Similarly, intraperitoneal estrogen administration induces tyrosine phosphorylation of STAT3 in the hypothalamus in less than 30 min [61].”

“Consistent with numerous previous reports [22], [41], [75], [93], [163], [164],[165] and [168], OVX results in a rapid increase in food intake and body weight relative to sham operated females, and this behavioral response is abolished by estradiol treatment alone [6].”

“Obesity is a leading cause for the development of adverse metabolic effects, including non-insulin dependent diabetes mellitus, dyslipidemia, and cardiovascular disease [34] and [45].”

“Leptin levels are inversely correlated with testosterone [69], [82], [98], [160] and [162] and exposure of human fat cells to testosterone or dihydrotestosterone inhibits leptin expression [162].”

“In aging and obese men, there is increased aromatase activity and conversion of androgens to estrogen and this is associated with increased plasma leptin [72], [115] and [175].”

“Consistent with numerous previous reports [22], [41], [75], [93], [163], [164],[165] and [168], OVX results in a rapid increase in food intake and body weight relative to sham operated females, and this behavioral response is abolished by estradiol treatment alone [6].”

“Intra-abdominal fat is relatively insensitive to insulin [23] and [104], and insulin action is markedly impaired in individuals with visceral obesity [26] and [121].”

“, increased food intake, decreased energy expenditure, and increased body weight) [145] and [170].”

“While both leptin and insulin cross into the brain via dedicated transport processes to act on specific receptors to regulate energy balance and elicit net catabolic responses, there are sexually dimorphic responses to their actions [29], [30] and [65].”

“After menopause and the decline of estrogen, women develop increased intra-abdominal adiposity, but those who receive estrogen replacement therapy do not [59], [63] and [64], suggesting a specific role of estrogen in limiting intraabdominal fat mass [10] and [31].”

“female—The increasing prevalence of obesity throughout the world [51], [122] and [127] is associated with an escalating incidence of obesity-related disorders and health costs [5].”

“Premenopausal women have lower activity of lipoprotein lipase in their intra-abdominal adipose tissue than men [132,133].”

“As previously mentioned, on average, women carry more fat subcutaneously [42], [66],[80], [89] and [90]; whereas men carry more fat viscerally [167].”

“Intra-abdominal adipose tissue has adipogenic, metabolic, pro-atherogenic, and pro-thrombotic characteristics [86], [112] and [158].”

“female—The increasing prevalence of obesity throughout the world [51], [122] and [127] is associated with an escalating incidence of obesity-related disorders and health costs [5].”

“Comparable phenomenon has been reported in a recent human study that men, but not women, lose body weight, body fat and waist circumference following intranasal insulin administration [65], an approach that increases insulin concentration of the cerebrospinal fluid and thereby alters brain functions [24].”

“Consistent with numerous previous reports [22], [41], [75], [93], [163], [164],[165] and [168], OVX results in a rapid increase in food intake and body weight relative to sham operated females, and this behavioral response is abolished by estradiol treatment alone [6].”

“Thus, men have greater risk to develop the metabolic syndrome as adiposity increases than premenopausal obese women do [36], [52] and [87].”

“In aging and obese men, there is increased aromatase activity and conversion of androgens to estrogen and this is associated with increased plasma leptin [72], [115] and [175].”

“Obesity is a leading cause for the development of adverse metabolic effects, including non-insulin dependent diabetes mellitus, dyslipidemia, and cardiovascular disease [34] and [45].”

“Additionally, when delivered directly into the central ventricular system, it decreases food intake possibly through its actions on the same neurons that are responsible for leptin’s anorectic responses [60].”

“Weight loss is characterized by an initial reduction in intra-abdominal rather than subcutaneous adipose tissue in part because intra-abdominal adipocytes are more metabolically active [12], [14], [16], [103], [110] and [166].”

“In addition, circulating free fatty acids are directly taken up and stored via a lipoprotein lipaseindependent pathway [9], [32] and [142].”

“Consistent with this hypothesis estrogen deficiency impairs central leptin sensitivity [3], [29] and [30].”

“Leptin is secreted at a higher rate from subcutaneous fat than from visceral fat [28] and [113], thus circulating leptin correlates better with total subcutaneous fat than with total body fat [30], [35], [42], [57], [76], [106], [126], [140] and [141].”

“Gonadal / sex steroids have been proposed as regulators of fat distribution [47] and [48].”

“Leptin levels are inversely correlated with testosterone [69], [82], [98], [160] and [162] and exposure of human fat cells to testosterone or dihydrotestosterone inhibits leptin expression [162].”

“Rapid, non-genomic actions of estradiol also have been described and some of them appear to involve ERα [1] and [108].”

“Estrogen regulates adiposity—Visceral fat varies inversely with estrogen levels [12], [13], [15], [25] and [49].”

“Syndecan-3 is a cell surface molecule found in the hypothalamus which facilitates the blockade of melanocortin receptors MC3/4R by the endogenous melanocortin antagonist agouti-related protein [135].”

“Hence, there are sex-based differences with regard to obesity-associated health risks with obese men being more likely to develop secondary metabolic complications and cardiovascular diseases than obese women [36], [83], [87], [92] and [169].”

“decrease in food intake during estrus in ovarian-intact, cycling rats [44,155].”

“Ovariectomy has been reported to cause a marked reduction in expression of long form of the leptin receptor in the hypothalamus and estradiol replacement restores its expression [109], suggesting development of leptin resistance when estrogen is Shi et al.”

“Subcutaneous adipose tissue has higher concentrations of ER and PR; however, visceral adipose tissue has higher concentrations of AR [97].”

“Estrogen regulates food intake—The preovulatory rise in estradiol secretion is associated with a decrease in food intake during estrus in ovarian-intact, cycling rats [44] Shi et al.”

“Therefore subcutaneous fat could be insulin sensitive tissue, through an elevated lipoprotein lipase activity that favors the clearance of circulating triglycerides of dietary origin and facilitates free fatty acid storage in adipocytes [81], [105], [147] and [161].”

“In today’s society there is an increase in the prevalence of obesity and its related metabolic diseases in adolescents and it is significantly higher among males than females aged 12 to 18 years [54], [70] and [154].”

“Specifically catecholamines stimulate lipolysis via b1-, b2- and b3-adrenoceptors and inhibit lipolysis via a2-adrenoceptors [27,85].”

“Weight loss is characterized by an initial reduction in intra-abdominal rather than subcutaneous adipose tissue in part because intra-abdominal adipocytes are more metabolically active [12], [14], [16], [103], [110] and [166].”

“Specifically, adipose tissue distributed in the abdominal or visceral region carries a much greater risk for metabolic disorders, than does adipose tissue distributed subcutaneously [19], [20] and [21].”

“Lipolysis correlates positively with activation of the sympathetic nervous system [4] which may further enhance free fatty acid release into portal circulation [95].”

“Further supporting a role for estrogen signaling through ERα in the regulation of body weight are the findings that abnormal adiposity has been associated with the XbaI polymorphism of the human ERα gene, in which guanidine is substituted for adenine in exon one of the [125], [152] and [173].”

“As previously mentioned, on average, women carry more fat subcutaneously [42], [66],[80], [89] and [90]; whereas men carry more fat viscerally [167].”

“Using fatty acid tracers in food and adipose tissue biopsies, Jensen and colleagues found a higher proportion of dietary fat is stored in the lower body gluteal / femoral subcutaneous adipose tissue in women than men [139].”

“Estrogen also activates the PI3K signaling cascade [100] and [101].”

“In women, leptin fluctuations during the menstrual cycle directly correlate with estrogen, but not with progesterone [102], [129] and [130].”

“Leptin is secreted at a higher rate from subcutaneous fat than from visceral fat [28] and [113], thus circulating leptin correlates better with total subcutaneous fat than with total body fat [30], [35], [42], [57], [76], [106], [126], [140] and [141].”

“Further supporting a role for estrogen signaling through ERα in the regulation of body weight are the findings that abnormal adiposity has been associated with the XbaI polymorphism of the human ERα gene, in which guanidine is substituted for adenine in exon one of the [125], [152] and [173].”

“Most women with polycystic ovary syndrome (PCOS), a hyperandrogenic disorder, have increased abdominal fat [37].”

“Upper body abdominal subcutaneous adipose tissue takes up free fatty acid and stores lipid more avidly than lower body gluteal/femoral subcutaneous adipose tissue in men [147].”

“Leptin levels are inversely correlated with testosterone [69], [82], [98], [160] and [162] and exposure of human fat cells to testosterone or dihydrotestosterone inhibits leptin expression [162].”

“Thus, men have greater risk to develop the metabolic syndrome as adiposity increases than premenopausal obese women do [36], [52] and [87].”

“Leptin levels are higher in females, even before puberty, compared with males [35].”

“In today’s society there is an increase in the prevalence of obesity and its related metabolic diseases in adolescents and it is significantly higher among males than females aged 12 to 18 years [54], [70] and [154].”

“These differences are presumably due to differential evolutionary and sexual selection pressures [68].”

“In humans, lipolytic response of abdominal subcutaneous adipose tissue to norepinephrine, an adrenergic agonist, is greater in obese women, whereas obese men have greater abdominal α2 receptor antilipolytic function than women [91].”

“, free fatty acid uptake) than comparable fat tissue from men [46]; in vitro catecholamine-induced lipolysis is significantly lower in subcutaneous gluteal adipocytes than in abdominal adipocytes from women, but are comparable between these adipocytes from men [136].”

“Hypothalamic cells that are immunoreactive for estrogen receptors also express leptin receptors [38].”

“Estrogen (ER), progesterone (PR), and androgen receptors (AR) are expressed in adipose tissues [33], [111] and [128].”

“In addition, circulating free fatty acids are directly taken up and stored via a lipoprotein lipaseindependent pathway [9], [32] and [142].”

“In contrast, excess adiposity in the gluteal / femoral subcutaneous region (‘gynoid’ or female-pattern) is poorly correlated with risk for these metabolic disorders [18], [39], [40], [88] and [123].”

“Excess adiposity in the central visceral region of the body (‘android’ or male-pattern obesity [167]) is correlated with increased risk and mortality from disorders including diabetes, hyperlipidemia, hypertension, and atherosclerosis [11], [56] and [73].”

“Estrogen regulates adiposity—Visceral fat varies inversely with estrogen levels [12], [13], [15], [25] and [49].”

“Specifically, females but not males decrease oxygen consumption and thermogenesis during [151] and [159] or after lipectomy [151], whereas males respond by eating more food when food is returned following CR or lipectomy [151].”

“A recent study reported that total body fat percentage of age-matched women is significantly higher in the perimenopausal and postmenopausal groups with decreased estrogen levels than in the premenopausal group [62] and [114].”

“Body weight regulation is thought to occur through negative feedback mechanisms which characterize most homeostatic systems [43], [131], [144], [146] and [172] involving adiposity signals.”

“of consuming less high-fat diet while females maintain their leanness by expending more energy [153].”

“In male rats, dihydrotestosterone decreases adipose tissue leptin mRNA, whereas in female rats, 17-β estradiol increases adipose tissue leptin mRNA levels [82].”

“Consistent with numerous previous reports [22], [41], [75], [93], [163], [164],[165] and [168], OVX results in a rapid increase in food intake and body weight relative to sham operated females, and this behavioral response is abolished by estradiol treatment alone [6].”

“Consistent with numerous previous reports [22], [41], [75], [93], [163], [164],[165] and [168], OVX results in a rapid increase in food intake and body weight relative to sham operated females, and this behavioral response is abolished by estradiol treatment alone [6].”

“Women have a greater number of antilipolytic a2-adrenoceptors in the gluteal/femoral subcutaneous region [136].”

“In addition, circulating free fatty acids are directly taken up and stored via a lipoprotein lipaseindependent pathway [9], [32] and [142].”

“Estrogen also activates the PI3K signaling cascade [100] and [101].”

“Surgical removal of intra-abdominal adipose tissue results in decreased insulin and glucose levels in humans [156]; improves glucose tolerance in male and female mice [150]; and prevents the onset of age-dependent insulin resistance and glucose intolerance in male rats [58].”

“Additionally, POMC Lepr-KO females accumulate greater percentage of visceral adipose tissue than male POMC Lepr-KO mice do [149].”

“In aging and obese men, there is increased aromatase activity and conversion of androgens to estrogen and this is associated with increased plasma leptin [72], [115] and [175].”

“Visceral adipose tissue uptake of triglyceride fatty acids is greater in men than in women [119].”

“When overfed voluntarily with a palatable high fat diet chronically [137] or acutely [138], female rats gain more body weight than males due to greater conservation of energy expenditure with lower activation of thermogenesis in brown adipose tissue combined with lower energy intake.”

“After menopause and the decline of estrogen, women develop increased intra-abdominal adiposity, but those who receive estrogen replacement therapy do not [59], [63] and [64], suggesting a specific role of estrogen in limiting intraabdominal fat mass [10] and [31].”

“In a separate model, both male and female mice with targeted disruption of the gene encoding granulocyte macrophage-colony stimulating factor show greater fat mass, and the mechanism is again sexually dimorphic with the males showing pronounced increase in intake while females have greater decreases in expenditure [13…”

“In contrast to what was previously reported for intra-abdominal adipose tissue, catecholamine-mediated lipolytic activity and free fatty acid release from subcutaneous adipose tissue is lower in women than in men [71].”

“Consistent with numerous previous reports [22], [41], [75], [93], [163], [164],[165] and [168], OVX results in a rapid increase in food intake and body weight relative to sham operated females, and this behavioral response is abolished by estradiol treatment alone [6].”

“Specifically catecholamines stimulate lipolysis via β1-, β2and β3-adrenoceptors and inhibit lipolysis via α2-adrenoceptors [27] and [85].”

“Leptin is secreted from adipose tissue, enters the brain from the blood, and interacts with specific receptors on neurons in the hypothalamus and other areas [2,145,171].”

“Leptin receptor expression levels are lowest in proestrus, the point of the estrus cycle with the highest levels of estradiol, in the choroid plexus, and these changes correspond inversely with levels of circulating estradiol over the 4-day estrous cycle in the rat [8].”

“Further supporting a role for estrogen signaling through ERα in the regulation of body weight are the findings that abnormal adiposity has been associated with the XbaI polymorphism of the human ERα gene, in which guanidine is substituted for adenine in exon one of the [125], [152] and [173].”

“women [81,105,147,161].”

“Intra-abdominal fat is relatively insensitive to insulin [23] and [104], and insulin action is markedly impaired in individuals with visceral obesity [26] and [121].”

“Estrogen (ER), progesterone (PR), and androgen receptors (AR) are expressed in adipose tissues [33], [111] and [128].”

“In rats this means that subcutaneous fat increases till day 12 of gestation, and declines progressively thereafter following gestation and lactation as it is utilized to provide energy; whereas visceral fat depots including lumbar and mesenteric adipose tissues progressively increase till the 19th day of gestation [96…”

“When overfed voluntarily with a palatable high fat diet chronically [137] or acutely [138], female rats gain more body weight than males due to greater conservation of energy expenditure with lower activation of thermogenesis in brown adipose tissue combined with lower energy intake.”

“Specifically, females but not males decrease oxygen consumption and thermogenesis during [151] and [159] or after lipectomy [151], whereas males respond by eating more food when food is returned following CR or lipectomy [151].”

“In contrast, excess adiposity in the gluteal / femoral subcutaneous region (‘gynoid’ or female-pattern) is poorly correlated with risk for these metabolic disorders [18], [39], [40], [88] and [123].”

“A recent study reported that total body fat percentage of age-matched women is significantly higher in the perimenopausal and postmenopausal groups with decreased estrogen levels than in the premenopausal group [62] and [114].”

“In addition, the decrease of α2/β3-adrenoceptor ratio is greater in males than females, which leads to a greater amount of fat accumulation in males fed with a high-fat diet [94].”

“Consistent with numerous previous reports [22], [41], [75], [93], [163], [164],[165] and [168], OVX results in a rapid increase in food intake and body weight relative to sham operated females, and this behavioral response is abolished by estradiol treatment alone [6].”

“subcutaneous fat—The increased health risks due to obesity vary depending on the location / accrual of adipose tissue [15], [16], [17], [19] and [123].”

“If age and body mass index (BMI) are matched, women have lower waist-to-hip ratio, indicating a greater amount of subcutaneous adipose tissue than men do [95] and [117].”

“In contrast, in obese women the efficiency of free fatty acid storage is greater in lower body gluteal/femoral subcutaneous than upper body abdominal subcutaneous fat [81,147].”

“Gonadal/sex steroids have been proposed as regulators of fat distribution [47,48].”

“ment therapy do not [59,63,64], suggesting a specific role of estrogen in limiting intra-abdominal fat mass [10,31].”

“The “classical” nuclear ER was cloned in 1985 [107] and renamed ERα when a second nuclear ER, ERβ, was discovered ten years later [84].”

“After menopause and the decline of estrogen, women develop increased intra-abdominal adiposity, but those who receive estrogen replacement therapy do not [59], [63] and [64], suggesting a specific role of estrogen in limiting intraabdominal fat mass [10] and [31].”

“Body weight regulation is thought to occur through negative feedback mechanisms which characterize most homeostatic systems [43], [131], [144], [146] and [172] involving adiposity signals.”

“tems [43,131,144,146,172] involving adiposity signals.”

“Sex differences in body fat composition and distribution, energy expenditure, orosensory physiology, taste and smell preference, food intake, binge eating, susceptibility to diet induced obesity, responses to leptin-, ghrelin,- or insulin- induced hyperphagia, POMC gene expression in the ARC nucleus, and many other tr…”

“Because excellent reviews of sex differences in the regulation of food intake and body weight have been recently published [6,7], in this review, we focus on physiologic and genetic determinants of sex differences in fat distribution.”

“…Grove et al., 2010; Karastergiou et al., 2013), developmental lineage (Chau et al., 2014; Krueger et al., 2014; Sanchez-Gurmaches and Guertin, 2014), metabolic characteristics (Cohen et al., 2014; Karastergiou and Fried, 2013; Tran et al., 2008), and adipokine secretion profiles (Shi et al., 2009).”

“Second, there are fundamental aspects of energy metabolism that are regulated differently in males and females [4].”

“Key mechanisms that have been implicated include effects of gonadal hormone–dependent and –independent sex differences in regional adipose tissue distribution, production of cytokines and adipokines, hepatic gluconeogenesis and glycogenolysis, and glucose uptake by skeletal muscle (1, 86, 102).”

“believed to be responsible in part for the dramatic sex differences in IR (Shi et al., 2009).”

“Although obesity affects both males and females, there is a sexual dimorphism in the development of metabolic complications associated with obesity (Shi et al., 2009; Sugiyama and Agellon, 2012).”

“Marked sex differences have been reported with regard to degrees of insulin resistance, body composition, and energy balance (49).”

“…fat increases until day 12 of gestation and declines progressively until lactation, when it is utilized to provide energy; visceral fat deposits, including lumbar and mesenteric adipose tissues, progressively increase until the 19th day of gestation (Lopez-Luna et al., 1991; Shi et al., 2009).”

“Most sex differences in humans are attributed to effects of gonadal hormones (4, 5).”

“differences might reflect the distinct, sex-dependent metabolic activity of omental and subcutaneous adipose tissue [54].”

“For instance, oestrogen, the predominant sex steroid in females, can exert effects on LPL to alter lipid accumulation, playing an essential role in fat distribution (Shi et al. 2009) and leading to greater inguinal fat deposition in females (Bjorntorp 1996; Pedersen et al. 2004).”

“Indeed, the adult function of the melanocortin system shows substantial sex differences, with females having increased responsiveness to theanorecticeffectsof leptinanddecreasedresponsiveness to the anorectic effects of insulin (20, 21).”

“Specifically, estrogen receptor alpha (ERα/ERS1), estrogen receptor beta (ERβ/ERS2), aswell as G protein-coupled estrogen receptor (GPER) have been demonstrated to regulate energy homeostasis (Brown and Clegg, 2010; Mauvais-Jarvis et al., 2013; Sharma et al., 2013; Shi et al., 2009).”

“Given the consequence of chronic stress on emotional changes including anxiety and depression (Berry et al., 2012), it is not surprising that there is a strong association between psychiatric disorders including anxiety and depression, and obesity in humans (Siervo et al., 2009).”

“Importantly, with loss of estrogens after menopause, females often begin storing more VAT and have higher risk of metabolic diseases, more like males (1, 19, 20).”

“A common theme appears to be that body weight regulation in males is more dependent on modulation of food intake whereas weight regulation in females is more dependent on modulation of energy expenditure [42].”

“A recently proposed model of the central and peripheral effects of leptin and estrogens provides a potential resolution to this disparity (Shi et al. 2009).”

“Available data suggest a clear gender difference in age-related changes in the body fat distribution, especially in abdominal adipose tissue, with a marked increase in visceral fat accumulation occurring after menopause [18,26,27].”

“…suggest that there is also a definite difference between sexes in age-related changes of whole-body fat distribution, especially in the abdominal fat tissues, and that the accumulation of visceral fat is markedly accelerated after menopause (Toth et al., 2000; Poehlman, 2002; Shi et al., 2009).”

“Circulating levels of many cytokines differ, as well as adipokine levels such as adiponectin and leptin (markedly higher in female mice compared with male mice) (Shi et al., 2009; Trujillo and Scherer, 2006).”

“Furthermore, estrogenwas found to protect premenopausal females from the adverse effects of obesity and metabolic complications of inflammation, such as cardiovascular disease (Shi et al., 2009; Morselli et al., 2014).”

“Specifically males are more responsible for hunting and gathering, while females are responsible for gestation, lactation and care-giving, and both must maintain energy homeostasis to support the survival and development of themselves as well as their offspring [2].”

“Previous reports have indicated that the innervation of abdominal WAT is generally greater than that to subcutaneous WAT (Shi et al., 2009).”

“to anti-inflammatory effects of estrogens and differential regulation of energy homeostasis between sexes [33, 106].”

“In general, excess adiposity in the central visceral region of the body (usually typical for male obesity) is correlated with increased risk and mortality from metabolic disorders (Shi et al., 2009).”

“It was demonstrated in a 4ear longitudinal observational study that subcutaneous fat mass ignificantly increases over time but only postmenopausal women howed an significant increase in visceral fat mass [5], which has een attributed to estrogen effects on lipolysis and lipogenesis in isceral adipocytes [7] and the SH…”

“However, in close analogy to what is observed in WAT and already reviewed (Haifei et al. 2009), sex hormones may also indirectly regulate BAT activity by their ability to modulate different metabolic pathways controlling energy homeostasis.”

“have reported sex differences in energy homeostasis [58].”

“Like leptin, the class of gonadal steroid estrogens also exerts a potent influence on energy balance, adiposity and glucose homeostasis [9].”

“All those acknowledged have agreed to be listed.”

“Gender-specific differences exist also in the relative importance of signaling by leptin or insulin to body weight regulation, with leptin playing a more prominent role in females (Clegg et al., 2003; Shi et al., 2009).”

“Gene expression contributes to diet-induced sex-specific weight gain and fat distribution in both humans and laboratory animal models [137,138].”

“Female’s metabolism and energy balance were influenced by estrogen [27–30], especially during proestus-estrus when endogenous estrogen is high and has greatest physiological effects [31].”

“The differences in metabolic rate [52–54] and energy homeostasis between males and females is dependent on actions of sex hormones [55–57] and expression of ER receptors in different tissues, including muscle [56,58] and adipose [59–65].”

“such as estrogens, androgens, glucocorticoids and growth hormones [5,6].”

“Estrogens are suggested to stimulate lipolysis and inhibit lipogenesis in visceral adipocytes via stimulation of the estrogen receptor alpha, thus limiting fat storage in visceral adipocytes in premenopausal women (Shi et al., 2009).”

“Thus, metabolic diseases are less prevalent among premenopausal women [32] and hormone-related differences in regional fat distribution and function obviously play a crucial role in this context [33] Furthermore, two hormonal intervention studies, the Women’s Health Initiative Study [34] and the Heart and Oestrogen/Pr…”

“Both male and female Scly KO mice presented similar aggravated obesity; however, we selected male mice to be further analyzed in our study, as gender-specific mechanisms were found to regulate energy metabolism (58) and selenium metabolism (33, 54).”

“Both testosterone and estrogen levels have been associated with components of MetS [76], and ovarian hormones, such as estrogen, have been suggested to have a protective role regarding MetS, at least before menopause [77].”

“Additionally, as it is well established that there are sexual differences in the control of energy homeostasis [17], we also uncovered critical gender differences in the Nur77 signaling by using male and female mice lacking Nur77 fed with a HFD of 45% calories from fat.”

“The mechanistic explanation for the observed sex difference is beyond the scope of the current study, but known sex differences in metabolic regulation (22) and the interaction of sex hormones with food intake, activity and metabolic rate are likely to play an important role.”

“In 57 ovariectomized rodent models, E2 regulates many aspects of energy homeostasis through both 58 peripheral actions and central mechanisms (reviewed in Mauvais-Jarvis et al., 2013; Roepke, 59 2009; Shi et al., 2009).”

“8% for Leptin [55], 39% for Stromelysin-1 (MMP3) [51, 56], 36.”

“As considerable data indicate that estrogen protects against weight gain [32,33], it seems plausible that ZEB1 might mediate estrogen’s effects on adiposity.”

“This may represent divergence in adipose content because females have been shown to have higher adiposity than males (41), and NEFA levels exhibit a positive correlation with fat levels (42).”

“Visceral fat varies inversely with estrogen levels [36], and the cessation of gonadal estrogen production at menopause is associated with the emergence of a more android pattern [31].”

“Previous reports have shown that the deficiency of estrogens or estrogen receptors results in visceral fat accumulation, impairment of insulin sensitivity and lipid metabolism, hypercholesterolemia, and cardiovascular disease risk [77,78].”

“However, after menopause, when estrogen levels in women decrease, these disorders become more prevalent in females [Shi et al., 2009].”

“tissue distribution and adiposity, which may translate to differences in the prevalence of metabolic syndrome and type 2 diabetes [13, 14].”

“Estrogen and testosterone modulate leptin synthesis and secretion [61].”

“Consistent with previous reports, WT females were protected from HF diet-induced obesity (34,35).”

“believed that the protective effect of the obesity-related metabolic disorder might be attributed to sex hormones, especially estrogen [38].”

“These patterns are not limited to rodents as sex differences in energy expenditure regulation are conserved across species, including humans [49, 153, 164].”

“Sex-dependent differences in energy intake, storage, and expenditure are well known, and these physiological mechanisms are under the control of sex hormones (43).”

“Differences in gene expression between subcutaneous and visceral fat are known [17] and our observation that KISS1 expression is 2.”