Anti-obesogenic and hypolipidemic effects of a glucagon-like peptide-1 receptor agonist derived from the saliva of the Gila monster.

INTRODUCTION: Glucagon-like peptide-1 (GLP-1) receptor (R) agonists are a class of incretin mimetic drugs that have been used for the treatment of type 2 diabetes mellitus and also considered strong candidates for the treatment of obesity. The original prototypical drug in this class is the exenatide, a synthetic peptide with the same structure as the native molecule, exendin-4, found in the saliva of the Gila monster (Heloderma suspectum suspectum lizard). OBJECTIVES: To identify and compare the anti-obesogenic, antidyslipidemic and antidiabetogenic effects of agonism in GLP-1R by exenatide on two distinct models of obesity: induced by hypothalamic injury (MSG) or high-calorie diet (DIO). METHODS: To obtain MSG, neonatal rats were daily subcutaneously injected with 4 g monosodium glutamate/kg, for 10 consecutive days. To obtain DIO, 72-75 days old rats received hyperlipid food and 30% sucrose for drinking up to 142-145 days old. Untreated healthy rats with the same age were used as control. General biometric and metabolic parameters were measured. RESULTS: MSG was characterized by decreased naso-anal length, food and fluid intake, plasma protein and glucose decay rate per minute after insulin administration (KITT), as well as increased Lee index (body mass0.33/naso-anal length), mass of retroperitoneal and periepididymal fat pads, glycemia, triglycerides (TG), LDL and VLDL. Exenatide ameliorated KITT and food and fluid intake, and it also restored glycemia in MSG. DIO was characterized by glucose intolerance, increased body mass, Lee index, fluid intake, mass of retroperitoneal and periepididymal fat pads, glycemia, glycated hemoglobin (HbA1c), TG, VLDL and total cholesterol, as well as decreased food intake and KITT. Exenatide restored glycemia, HbA1c, TG, VLDL, total cholesterol and body mass, and it also ameliorated food and fluid intake, KITT and mass of retroperitoneal fat pad in DIO. CONCLUSIONS: The hypothalamic injury and the high-calorie diet induce dyslipidemia and glycemic dysregulation in addition to obesity in rats. The usual therapeutic dose of exenatide in humans is antidiabetogenic in both these obesity models, but is anti-obesogenic and hypolipidemic only in diet-induced obesity. Agonists of GLP-1R are promising anti-obesogenic and antidyslipidemic drugs in the early stages of the obesity, in which the integrity of the nervous system was unaffected.

Dipeptidyl peptidase IV in the hypothalamus and hippocampus of monosodium glutamate obese and food-deprived rats.

Proline-specific dipeptidyl peptidases are emerging as a protease family with important roles in the regulation of signaling by peptide hormones related to energy balance. The treatment of neonatal rats with monosodium glutamate (MSG) is known to produce a selective damage on the arcuate nucleus with development of obesity. This study investigates the relationship among dipeptidyl peptidase IV (DPPIV) hydrolyzing activity, CD26 protein, fasting, and MSG model of obesity in 2 areas of the central nervous system. Dipeptidyl peptidase IV and CD26 were, respectively, evaluated by fluorometry, and enzyme-linked immunosorbent assay and reverse transcriptase polymerase chain reaction in soluble (SF) and membrane-bound (MF) fractions from the hypothalamus and hippocampus of MSG-treated and normal rats, submitted or not to food deprivation (FD). Dipeptidyl peptidase IV in both areas was distinguished kinetically as insensitive (DI) and sensitive (DS) to diprotin A. Compared with the controls, MSG and/or FD decreased the activity of DPPIV-DI in the SF and MF from the hypothalamus, as well as the activity of DPPIV-DS in the SF from the hypothalamus and in the MF from the hippocampus. Monosodium glutamate and/or FD increased the activity of DPPIV-DI in the MF from the hippocampus. The monoclonal protein expression of membrane CD26 by enzyme-linked immunosorbent assay decreased in the hypothalamus and increased in the hippocampus of MSG and/or FD relative to the controls. The existence of DPPIV-like activity with different sensitivities to diprotin A and the identity of insensitive with CD26 were demonstrated for the first time in the central nervous system. Data also demonstrated the involvement of DPPIV-DI/CD26 hydrolyzing activity in the energy balance probably through the regulation of neuropeptide Y and ß-endorphin levels in the hypothalamus and hippocampus.

Hypothalamic activity during altered salt and water balance in the snake Bothrops jararaca.

The effects of water and salt overload on the activities of the supraoptic and paraventricular nuclei and the adjacent periventricular zone of the hypothalamus of the snake Bothrops jararaca were investigated by measurements of Fos-like immunoreactivity (Fos-ir). Both water and salt overload resulted in changes in body mass, plasma osmolality, and plasma concentrations of sodium, potassium, and chloride. Hyper-osmolality increased Fos immunoreactivity in the rostral supraoptic nucleus (SON), the paraventricular nucleus (PVN), and adjacent periventricular areas. Both hyper- and hypo-osmolality increased Fos immunoreactivity in the intermediate SON, but not in other areas of the hypothalamus. Immunostaining was abundant in cerebrospinal fluid (CSF)-contacting tanycyte-like cells in the ependymal layer of the third ventricle. These data highlight some features of regional distribution of Fos immunoreactivity that are consistent with vasotocin functioning as a hormone, and support the role of hypothalamic structures in the response to disruption of salt and water balance in this snake.