The role of 5-HT2c receptor on corticosterone-mediated food intake.

Corticosterone plays an important role in feeding behavior. However, its mechanism remains unclear. Therefore, the present study aimed to investigate the effect of corticosterone on feeding behavior. In this study, cumulative food intake was increased by acute corticosterone administration in a dose-dependent manner. Administration of the 5-HT2c receptor agonist m-chlorophenylpiperazin (mCPP) reversed the effect of corticosterone on food intake. The anorectic effects of mCPP were also blocked by the 5-HT2c receptor antagonist RS102221 in corticosterone-treated mice. Both corticosterone and mCPP increased c-Fos expression in hypothalamic nuclei, but not the nucleus of the solitary tract. RS102221 inhibited c-Fos expression induced by mCPP, but not corticosterone. In addition, mCPP had little effect on TH and POMC levels in the hypothalamus. Furthermore, mCPP antagonized decreasing effect of the leptin produced by corticosterone. Taken together, our findings suggest that 5-HT2c receptors and leptin may be involved in the effects of corticosterone-induced hyperphagia.

Hypothalamic Leptin and Ghrelin Signaling as Targets for Improvement in Metabolic Control.

Metabolic homeostasis requires a tight balance between energy intake and energy expenditure; hence, the physiological circuits implicated in the regulation of energy metabolism must be able to quickly adjust to changes in either side of the equation. Circulating orexigenic and anorexigenic factors, including ghrelin and leptin, are produced in the gastrointestinal tract and adipose tissue, respectively, in relation to an individual's nutritional status. These signals interact with central metabolic circuits to regulate the production and secretion of neuropeptides implicated in the control of appetite and energy expenditure. However, this physiological equilibrium can be perturbed by diverse processes, with weight gain occurring due to a positive energy balance and weight loss taking place if there is a negative energy balance. If a situation of positive energy balance continues for an extended period of time, excess weight is accumulated and this can eventually result in obesity. Obesity has become one of the most important health problems facing the industrialized world, indicating that metabolic equilibrium is frequently disrupted. Understanding how and why this occurs will allow new therapeutical targets to be identified.

GLP-1/glucagon coagonism restores leptin responsiveness in obese mice chronically maintained on an obesogenic diet.

We recently reported restoration of leptin responsiveness in diet-induced obese (DIO) mice using a pharmacologically optimized, polyethylene-glycolated (PEG)-leptin analog in combination with exendin-4 or FGF21. However, the return of leptin action required discontinuation of high-fat diet (HFD) exposure. Here we assess whether a single peptide possessing balanced coagonism at the glucagon-like peptide 1 (GLP-1) and glucagon receptors can restore leptin responsiveness in DIO mice maintained on a HFD. DIO mice were treated with PEG-GLP-1/glucagon (30 nmol/kg every fourth day) to induce an ∼15% body weight loss, upon which they were randomized to continue PEG-GLP-1/glucagon therapy or reassigned to receive supplemental daily PEG-leptin (185 nmol/kg/day). The addition of PEG-leptin to PEG-GLP-1/glucagon resulted in an ∼18% greater weight loss as compared with PEG-GLP-1/glucagon alone and was accompanied by further decreases in food intake and improved glucose and lipid metabolism. The beneficial effect of PEG-leptin supplementation occurred after an initial body weight loss similar to what we previously reported following reduced dietary fat along with PEG-leptin and exendin-4 or FGF21 cotreatment. In summary, we report that GLP-1/glucagon coagonism restores leptin responsiveness in mice maintained on a HFD, thus emphasizing the translational value of this polypharmacotherapy for the treatment of obesity and diabetes.

Novel approaches to the treatment of obesity and type 2 diabetes mellitus: bioactive leptin-related synthetic peptide analogs.

Leptin, the protein product of the ob gene, is primarily an adipocyte-secreted hormone, whose functional significance is rapidly expanding. Although early research efforts were focused on defining leptin's role in reversing obesity in rodents, there is now substantial evidence indicating that its influence extends to a number of hypothalamic-pituitaryendocrine axes, including adrenal, gonadal, growth hormone, pancreatic islets, and thyroid. The pleiotropic nature of leptin has been confirmed by demonstration of a role for leptin in hematopoiesis, angiogenesis, immune function, osteogenesis, reproduction, and wound healing. Unfortunately, the results of the majority of clinical trials with recombinant human leptin indicated that its effectiveness in restoring energy balance and correcting obesity-related endocrinopathies in genetically obese rodent models extended only to the management of those rare forms of human obesity caused by mutation in the ob gene. Failure of leptin in the clinic, and withdrawal of phentermine from Europe, and fenfluramine and sibutrimine from clinical use in the United States, have stimulated new approaches in the development of anti-obesity and anti-diabetes pharmacophores. These efforts are focused on utilizing leptin-related synthetic peptides as leptin receptor antagonists or leptin-related synthetic peptide analogs or mimetics. This review summarizes patents on leptin-related peptide analogs, antagonists and mimetics.

Novel factors as therapeutic targets to treat diabetes. Focus on leptin and ghrelin.

BACKGROUND: Obesity is the major cause of type 2 diabetes. In the mid 1990s interest in adipose tissue was revived by the discovery of leptin. The association of obesity and diabetes emphasizes their shared physiopathological features. At the end of the 1990s, ghrelin, a potent gastric orexigenic factor, was found to be involved in obesity. Leptin and ghrelin have opposite actions in several tissues including the regulation of feeding in the brain. OBJECTIVE/METHODS: To survey the role of leptin and ghrelin in glucose metabolism. We summarize the current state of research and discuss the roles of ghrelin and leptin in glucose homeostases and the potential application of drugs targeting leptin and ghrelin signalling to prevent and treat diabetes. RESULTS/CONCLUSIONS: A pressing challenge is to determine how leptin, ghrelin and other adipokines or gastric factors are involved in metabolic disorders. Answering these questions will require the development of new pharmacological tools that target specific adipokine systems. Hopefully, new therapeutic targets will be identified.