Haifei Shi

Sexual differences in the control of energy homeostasis.

The prevalence of obesity has reached epidemic proportion with enormous costs in both human lives and healthcare dollars spent. Obesity-related metabolic disorders are much lower in premenopausal women than men; however, there is a dramatic increase following menopause in women. The health risks associated with obesity vary depending on the location of adipose tissue. Adipose tissue distributed in the abdominal visceral carry a much greater risk for metabolic disorders than does adipose tissue distributed subcutaneously. There are distinct sex-dependent differences in the regional fat distribution, women carry more fat subcutaneously whereas men carry more fat viscerally. Males and females differ with respect to their regulation of energy homeostasis. Peripheral adiposity hormones such as leptin and insulin as well as sex hormones directly influence energy balance. Sexual dimorphisms in energy balance, body fat distribution, and the role sex hormones have in mediating these differences are the focus of this review.

Sex differences in the regulation of body weight.

Obesity and its associated health disorders and costs are increasing. Males and females differ in terms of how and where body fat is stored, the hormones they secrete in proportion to their fat, and the way their brains respond to signals that regulate body fat. Fat accumulation in the intra-abdominal adipose depot is associated with the risk for developing cardiovascular problems, type-2 diabetes mellitus, certain cancers and other disorders. Men and postmenopausal women accumulate more fat in the intra-abdominal depot than do pre-menopausal women, and therefore have a greater risk of developing metabolic complications associated with obesity. The goal of this review is to explore what we know about sexual dimorphisms in adipose tissue accrual and deposition. Elucidating the mechanisms by which sex hormones may modulate the way in which fat is accumulated and stored is a critical area of research due to the prevalence of obesity and the metabolic syndrome, and the rapid increase in propensity for these diseases following menopause.

Sexually different actions of leptin in proopiomelanocortin neurons to regulate glucose homeostasis.

Leptin regulates energy balance and glucose homeostasis, at least in part, via activation of receptors in the arcuate nucleus of the hypothalamus located in proopiomelanocortin (POMC) neurons. Females have greater sensitivity to central leptin than males, suggested by a greater anorectic effect of central leptin administration in females. We hypothesized that the regulation of energy balance and peripheral glucose homeostasis of female rodents would be affected to a greater extent than in males if the action of leptin in POMC neurons were disturbed. Male and female mice lacking leptin receptors only in POMC neurons gained significantly more body weight and accumulated more body fat. However, female mice gained disproportionately more visceral adiposity than males, and this appeared to be largely the result of differences in energy expenditure. When maintained on a high-fat diet (HFD), both male and female mutants had higher levels of insulin following exogenous glucose challenges. Chow- and HFD-fed males but not females had abnormal glucose disappearance curves following insulin administrations. Collectively, these data indicate that the action of leptin in POMC neurons is sexually different to influence the regulation of energy balance, fat distribution, and glucose homeostasis.

The roles of leptin receptors on POMC neurons in the regulation of sex-specific energy homeostasis.

Leptin regulates energy homeostasis and reproduction. One key population of leptin receptors (Lepr) are found on proopiomelanocortin (POMC) neurons in the hypothalamic arcuate nucleus, and evidence links the action of gonadal estrogens to these same POMC neurons. To determine whether Lepr on POMC neurons are critical for reproductive capacity or for sex-specific energy and glucose homeostasis, we studied Cre/loxP mice lacking Lepr specifically on POMC neurons (Pomc-Cre, Lepr(flox/flox) mice) and their controls with normal Lepr (Lepr(flox/flox) mice). Pomc-Cre, Lepr(flox/flox) mice maintained normal reproductive capacity and accumulated more body fat than their same sex controls. Ovariectomy (OVX) was performed to investigate the effects of the estrogens and Lepr on POMC neurons on body fat accumulation and glucose tolerance. OVX Pomc-Cre, Lepr(flox/flox) females accumulated more fat than OVX Lepr(flox/flox) females did. Pomc-Cre, Lepr(flox/flox) males were glucose intolerant and insulin insensitive compared with control males. In contrast, control and Pomc-Cre, Lepr(flox/flox) females had similar glucose tolerance before and after OVX. Therefore leptins action on POMC neurons reduces body fat accumulation, but is not critical for regulation of reproduction. The sex difference in leptin signaling on POMC neurons on glucose tolerance appears independent of ovarian hormones.

Diet-induced Obese Mice Are Leptin Insufficient After Weight Reduction

Behavioral therapies aimed at reducing excess body fat result in limited fat loss after dieting. To understand the causes for maintenance of adiposity, high‐fat (HF) diet–induced obese (DIO) mice were switched to a low‐fat chow diet, and the effects of chow on histological and molecular alterations of adipose tissue and metabolic parameters were examined. DIO mice reduced and stabilized their body weights after being switched to chow (HF‐chow), but retained a greater amount of adiposity than chow‐fed mice. Reduction in adipocyte volume, not number, caused a decrease in fat mass. HF‐chow mice showed normalized circulating insulin and leptin levels, improved glucose tolerance, and reduced inflammatory status in white adipose tissue (WAT). Circulating leptin levels corrected for fat mass were lower in HF‐chow mice. Leptin administration was used to test whether reduced leptin level of HF‐chow mice inhibited further fat loss. Leptin treatment led to an additional reduction in adiposity. Finally, HF‐HF mice had lower mRNA levels of β3 adrenergic receptor (β3‐AR) in epididymal WAT (EWAT) compared to chow‐fed mice, and diet change led to an increase in the WAT β3‐AR mRNA levels that were similar to the levels of chow‐fed mice, suggesting an elevation in sympathetic activation of WAT during diet switch relative to HF‐HF mice leading to the reduced leptin level and proinflammatory cytokine content. In summary, HF‐chow mice were resistant to further fat loss due to leptin insufficiency. Diet alteration from HF to low fat improved metabolic state of DIO mice, although their adiposity was defended at a higher level.

Transplantation or removal of intra-abdominal adipose tissue prevents age-induced glucose insensitivity.

Increases in intra-abdominal fat, a common feature associated with aging, is an established risk factor for insulin resistance, diabetes and the metabolic syndrome. To examine the direct contribution of intra-abdominal fat in the pathophysiology of insulin resistance we altered fat volume via removal or transplantation in a naturally occurring age-induced moderate model of obesity and insulin resistance. This was accomplished by bilateral removal of epididymal white adipose tissue (Lipx) or transplantation of donor fat into the intra-abdominal side of the peritoneal cavity of 28-week old rats. Control animals received sham surgery. Glucose tolerance was evaluated at baseline and 4 and 8weeks post-surgery in all groups, and fasting insulin and leptin were additionally measured in 28-week old rats. In addition, fasted and fed triglyceride, cholesterol and fatty acid concentrations were measured. Before surgery 28-week old rats weighed more and were glucose intolerant compared with 8-week old controls. Both Lipx and transplantation significantly prevented age-induced decreases in glucose tolerance, with Lipx causing improvement at 4weeks which declined by 8weeks; and with a significant transplantation improvement at 8weeks only. Lipx significantly increased insulin secretion 15min after a bolus injection of 0.75mg/kg dextrose at 4 and 8weeks compared with controls, while transplantation caused a significant ( approximately 220%) increase in fasted leptin level at 4weeks only. Taken together, these data suggest that surgical removal or addition of intra-abdominal fat prevents age-induced insulin resistance by different mechanisms and is a suitable model to investigate naturally occurring obesity.

Removal of intra-abdominal visceral adipose tissue improves glucose tolerance in rats: Role of hepatic triglyceride storage ☆

Epidemiological studies have demonstrated a strong link between increased visceral fat and metabolic syndrome. In rodents, removal of intra-abdominal but non-visceral fat improves insulin sensitivity and glucose homeostasis, though previous studies make an imprecise comparison to human physiology because actual visceral fat was not removed. We hypothesize that nutrient release from visceral adipose tissue may have greater consequences on metabolic regulation than nutrient release from non-visceral adipose depots since the latter drains into systemic but not portal circulation. To assess this we surgically decreased visceral white adipose tissue (~0.5 g VWATx) and compared the effects to removal of non-visceral epididymal fat (~4 g; EWATx), combination removal of visceral and non-visceral fat (~4.5 g; EWATx/VWATx) and sham-operated controls, in chow-fed rats. At 8 weeks after surgery, only the groups with visceral fat removed had a significantly improved glucose tolerance, although 8 times more fat was removed in EWATx compared with VWATx. This suggests that mechanisms controlling glucose metabolism are relatively more sensitive to reductions in visceral adipose tissue mass. Groups with visceral fat removed also had significantly decreased hepatic lipoprotein lipase (LPL) and triglyceride content compared with controls, while carnitine palmitoyltransferase (CPT-1A) was decreased in all fat-removal groups. In a preliminary experiment, we assessed the opposite hypothesis; i.e., we transplanted excess visceral fat from a donor rat to the visceral cavity (omentum and mesentery), which drains into the hepatic portal vein, of a recipient rat but observed no major metabolic effect. Overall, our results indicate surgical removal of intra-abdominal fat improves glucose tolerance through mechanism that may be mediated by reductions in liver triglyceride.

Effects of energy status and diet on Bdnf expression in the ventromedial hypothalamus of male and female rats.

Sex differences exist in the regulation of energy homeostasis in response to calorie scarcity or excess. Brain-derived neurotrophic factor (BDNF) is one of the anorexigenic neuropeptides regulating energy homeostasis. Expression of Bdnf mRNA in the ventromedial nucleus of the hypothalamus (VMH) is closely associated with energy and reproductive status. We hypothesized that Bdnf expression in the VMH was differentially regulated by altered energy balance in male and female rats. Using dietary intervention, including fasting-induced negative energy status and high-fat diet (HFD) feeding-induced positive energy status, along with low-fat diet (LFD) feeding and HFD pair-feeding (HFD-PF), effects of diets and changes in energy status on VMH Bdnf expression were compared between male and female rats. Fasted males but not females had lower VMH Bdnf expression than their fed counterparts following 24-hour fasting, suggesting that fasted males reduced Bdnf expression to drive hyperphagia and body weight gain. Male HFD obese and HFD-PF non-obese rats had similarly reduced expression of Bdnf compared with LFD males, indicating that dampened Bdnf expression was associated with feeding a diet high in fat instead of increased adiposity. Decreased BDNF signaling during HFD feeding would increase a drive to eat and may contribute to diet-induced obesity in males. In contrast, VMH Bdnf expression was stably maintained in females when energy homeostasis was disturbed. These results suggest sex-distinct regulation of central Bdnf expression by diet and energy status.

Enhanced sympathetic activity in mice with brown adipose tissue transplantation (transBATation)

Brown adipose tissue (BAT) burns calories to produce heat, and is thus relevant to energy balance. Interscapular BAT (IBAT) of donor mice was transplanted into recipient mice (transBATation). To test whether transBATation counteracts high-fat diet (HFD)-induced obesity, some sham-operated and recipient mice were fed a HFD (HFD-sham, HFD-trans) while others remained on a standard chow (chow-sham, chow-trans). HFD-trans mice had lower body weight and fat and greater energy expenditure, but similar caloric intake compared with HFD-sham mice. We hypothesized that HFD-trans mice had elevated sympathetic activity compared with HFD-sham mice, contributing to increased energy expenditure and fuel mobilization. This was supported by findings that HFD-trans mice had greater energy expenditure during a norepinephrine challenge test and higher core temperatures after cold exposure than did HFD-sham mice, implicating enhanced whole-body metabolic response and elevated sympathetic activity. Additionally, transBATation selectively increased sympathetic drive to some, but not all, white adipose tissue depots and skeletal muscles, as well as the endogenous IBAT, heart, and liver. Collectively, transBATation confers resistance to HFD-induced obesity via increase in whole-body sympathetic activity, and differential activation of sympathetic drive to some of the tissues involved in energy expenditure and fuel mobilization.

The Effects of the Melanocortin Agonist (MT-II) on Subcutaneous and Visceral Adipose Tissue in Rodents

The melanocortin system is a critical pathway in the regulation of energy balance. In this study, we analyzed the peripheral effects of the synthetic melanocortin agonist melanotan-II (MT-II) in rodents fed a low-fat or high-fat diet. MT-II-treated high-fat diet-induced obese (DIO) mice lost weight and body fat, whereas MT-II-treated low-fat-fed mice maintained their original body weight. Specifically, MT-II treatment led to a general reduction in both visceral and subcutaneous adipose tissue in high-fat-fed mice compared with Vehicle (ad libitum) controls. Vehicle-treated pair-fed DIO mice lost an equivalent amount of body weight compared with MT-II-treated mice but retained more adipose tissue. Pair-fed mice showed a reduction in visceral adipose tissue and no effect on subcutaneous adipose tissue compared with MT-II-treated mice. It is surprising that subcutaneous lean mass was significantly reduced in the pairfed mice. The data were replicated in DIO rats and indicated that MT-II treatment led to a generalized reduction in adipose tissue. These results indicate that peripheral MT-II treatment leads to weight loss that affects both the visceral and subcutaneous fat compartments. This finding illustrates the complexity of analyzing weight-reducing compounds. Although the present data suggest that the anorectic effect of MT-II is primarily a consequence of reduced food intake, the body composition data suggest that other mechanisms are involved.