April D. Strader

Estradiol-dependent decrease in the orexigenic potency of ghrelin in female rats.

Ghrelin, the only known orexigenic gut hormone, is secreted mainly from the stomach, increases with fasting and before meal initiation in humans and rats, and increases food intake after central or peripheral administration. To investigate sex differences in the action of ghrelin, we assessed the effects of exogenous ghrelin in intact male and female rats, the effects of exogenous ghrelin in ovariectomized (OVX) and estradiol (E2)-treated female rats, as well as the effects of OVX on plasma ghrelin and hypothalamic orexigneic neuropeptide expression in rats and on food intake and weight gain in transgenic mice lacking the ghrelin receptor (Ghsr−/− mice). Male and OVX female rats were significantly more sensitive than intact female rats to the orexigenic effects of both centrally (intra–third ventricular, i3vt, 0.01, 0.1, and 1.0 nmol) and systemically (ip, 3, 6, and 9 nmol) administered ghrelin. This difference is likely to be estradiol dependent because E2 attenuated the orexigenic action of ghrelin in OVX female and male rats. Furthermore, OVX increased food intake and body weight in wild-type mice, but not in Ghsr−/− mice, suggesting that OVX increases food intake by releasing ghrelin from a tonic inhibitory effect of estradiol. In addition, following OVX, there was an increase in plasma ghrelin that was temporally associated with increased food intake, body weight, and hypothalamic neuropeptide Y and Agouti-related protein mRNA expression. Collectively, these data suggest that estradiol inhibits the orexigenic action of ghrelin in females, that weight gain associated with OVX is ghrelin mediated, and that this endocrine interaction may account for an important sex differences in food intake and the regulation of body weight.

Mice lacking the syndecan-3 gene are resistant to diet-induced obesity

The accurate matching of caloric intake to caloric expenditure involves a complex system of peripheral signals and numerous CNS neurotransmitter systems. Syndecans are a family of membrane-bound heparan sulfate proteoglycans that modulate ligand-receptor interactions. Syndecan-3 is heavily expressed in several areas of the brain, including hypothalamic nuclei, which are known to regulate energy balance. In particular, syndecans have been implicated in modulation of the activity of the melanocortin system, which potently regulates energy intake, energy expenditure, and peripheral glucose metabolism. Our data demonstrate that syndecan-3-null mice have reduced adipose content compared with wild-type mice. On a high-fat diet, syndecan-3-null male and female mice exhibited a partial resistance to obesity due to reduced food intake in males and increased energy expenditure in females relative to that of wild-type mice. As a result, syndecan-3-null mice on a high-fat diet accumulated less adipose mass and showed improved glucose tolerance compared with wild-type controls. The data implicate syndecan-3 in the regulation of body weight and suggest that inhibition of syndecan-3 may provide a therapeutic approach for the treatment of obesity resulting from exposure to high-fat diets.

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.

Syndecan‐3 Modulates Food Intake by Interacting with the Melanocortin/AgRP Pathway

Abstract: Syndecan‐3, expressed in the developing nervous system and adult brain, alters feeding behavior through its interaction with the CNS melanocortin system, which provides critical tonic inhibition of both food intake and body adipose stores. A variety of both in vitro and transgenic data supports the hypothesis that syndecan‐3 modulates melanocortin activity via syndecan‐3 facilitation of agouti‐related protein (AgRP), a competitive antagonist of α‐melanocyte‐stimulating hormone (α‐MSH) at the melanocortin‐3 and ‐4 receptors. Consistent with this hypothesis, mice lacking syndecan‐3, which therefore would be predicted to have less effective AgRP, are more sensitive to inhibition of food intake by the melanocortin agonist MTII. Additionally, we took advantage of the fact that syndecan‐3 facilitation of AgRP is limited to when it is bound to the cell membrane. Pharmacologic inhibition of the enzyme that cleaves syndecan‐3 from the cell membrane leads to increased food intake in fasted rats, which have elevated levels of AgRP. Furthermore, the shedding process appears to be regulated under physiologic conditions, because a putative inhibitor of the shedding process, tissue inhibitor of metalloprotease‐3 (TIMP‐3), is increased by food deprivation. These observations contribute to the hypothesis that syndecan‐3 regulation of melanocortin signaling contributes to the normal control of energy balance. Collectively, the data suggest that the modulation of melanocortin regulation of energy balance by syndecan‐3 is modulated by the action of a TIMP‐3‐sensitive metalloprotease.

Could the mechanisms of bariatric surgery hold the key for novel therapies?: report from a Pennington Scientific Symposium

Bariatric surgery is the most effective method for promoting dramatic and durable weight loss in morbidly obese subjects. Furthermore, type 2 diabetes is resolved in over 80% of patients. The mechanisms behind the amelioration in metabolic abnormalities are largely unknown but may be due to changes in energy metabolism, gut peptides and food preference. The goal of this meeting was to review the latest research to better understand the mechanisms behind the ‘magic’ of bariatric surgery. Replication of these effects in a non‐surgical manner remains one of the ultimate challenges for the treatment of obesity and diabetes. Promising data on energy metabolism, gastrointestinal physiology, hedonic response and food intake were reviewed and discussed.

Chronic food restriction and reduced dietary fat: Risk factors for bouts of overeating

The purpose of this study was to determine the effect of chronic food restriction and reduced dietary fat on feeding behavior and body weight. Young female rats were fed ad lib or food restricted on a low-fat (LF) or a fat-free (FF) diet for 4 weeks. Rats then received 24-h free access to 2 diets, the maintenance diet (LF or FF) plus a novel high-fat (HF) diet (24-h intake test). After the test, all the rats were allowed chronic free access to the HF diet until body weight was stable. During the 24-h test, the restricted groups ate significantly more calories than the ad lib groups, and the FF-restricted rats ate significantly more total food, carbohydrate and protein than the LF-restricted rats; there were no differences between the two ad lib groups. During chronic free access to the HF diet, the formerly restricted rats achieved and defended lower body weights than the formerly non-restricted rats. Throughout the experiment, the ad lib groups had more body fat than the restricted groups independent of the dietary subgroup. Hence, a history of chronic food restriction predisposes to consuming more food in acute feeding situations, particularly when dietary fat is reduced, and lowers the level of body weight maintained and defended. Chronic food restriction accompanied by reduced dietary fat may increase risk for bouts of overeating.

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.