Anti-obesogenic and hypolipidemic effects of a glucagon-like peptide- 1 receptor agonist derived from the saliva of the Gila monster Patricia Lucio Alves, Fernando Mauricio Francis Abdalla, Rafaela Fadoni Alponti, Paulo Flavio Silveira * Laboratory of Pharmacology, Unit of Translational Endocrine Physiology, Instituto Butantan, Sao Paulo, Brazil article info Article history: Received 26 April 2017 Received in revised form 31 May 2017 Accepted 1 June 2017 Available online 1 June 2017 Keywords: Obesity Dyslipidemia Incretin Drug repurposing Lizard toxin abstract 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, 72e75 days old rats received hyperlipid food and 30% sucrose for drinking up to 142e145 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 (K ITT ), as well as increased Lee index (body mass 0.33 /naso-anal length), mass of retroperitoneal and periepididymal fat pads, glycemia, triglycerides (TG), LDL and VLDL. Exenatide ameliorated K ITT 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 K ITT . Exenatide restored glycemia, HbA1c, TG, VLDL, total cholesterol and body mass, and it also ameliorated food and fluid intake, K ITT and mass of retroperitoneal fat pad in DIO. Conclusions: The hypothalamic injury and the high-calorie diet induce dyslipidemia and glycemic dys- regulation in addition to obesity in rats. The usual therapeutic dose of exenatide in humans is anti- diabetogenic 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. © 2017 Elsevier Ltd. All rights reserved. Abbreviations: AUC, area under the time-course curve of glycemia; DIO, obesity induced by high-calorie diet; DIO-E, obesity induced by high-calorie diet treated with exenatide; T2D, type 2 diabetes mellitus; EXE, exenatide; GLP-1, glucagon-like peptide-1; GLP-1R, glucagon-like peptide-1 receptor; GLUT4, glucose transporter type 4; HbA1c, glycated hemoglobin; HDL, high density lipoprotein cholesterol; ITT, insulin tolerance test; K ITT , glucose decay rate per minute after insulin administration; LDL, low density lipoprotein cholesterol; MSG, obesity induced by hypothalamic injury; MSG-E, obesity induced by hypothalamic injury treated with exenatide; OGTT, oral glucose tolerance test; TG, triglycerides; VLDL, very low density lipoprotein. * Corresponding author. Laboratory of Pharmacology, Instituto Butantan, Avenue Vital Brasil, 1500, CEP 05503-900, Sao Paulo, SP, Brazil. E-mail address: paulo.silveira@butantan.gov.br (P.F. Silveira). Contents lists available at ScienceDirect Toxicon journal homepage: www.elsevier.com/locate/toxicon http://dx.doi.org/10.1016/j.toxicon.2017.06.001 0041-0101/© 2017 Elsevier Ltd. All rights reserved. Toxicon 135 (2017) 1e11