Antiobesity action of peripheral exenatide (exendin-4) in rodents: effects on food intake, body weight, metabolic status and side-effect measures

Abstract

Background: Exenatide (exendin-4) is an incretin mimetic currently marketed as an antidiabetic agent for patients with type 2 diabetes. In preclinical models, a reduction in body weight has also been shown in low-fat-fed, leptin receptor-deficient rodents. Objective: To more closely model the polygenic and environmental state of human obesity, we characterized the effect of exenatide on food intake and body weight in high-fat-fed, normal (those with an intact leptin signaling system) rodents. As glucagon-like peptide-1 receptor agonism has been found to elicit behaviors associated with visceral illness in rodents, we also examined the effect of peripheral exenatide on kaolin consumption and locomotor activity. Methods and results: High-fat-fed C57BL/6 mice and Sprague-Dawley rats were treated with exenatide (3, 10 and 30 mg/kg/ day) for 4 weeks via subcutaneously implanted osmotic pumps. Food intake and body weight were assessed weekly. At 4 weeks, body composition and plasma metabolic profiles were measured. Kaolin consumption and locomotor activity were measured in fasted Sprague-Dawley rats following a single intraperitoneal injection of exenatide (0.1-10 mg/kg). Exenatide treatment in mice and rats dose-dependently decreased food intake and body weight; significant reductions in body weight gain were observed throughout treatment at 10 and 30 mg/kg/day (Po0.05). Decreased body weight gain was associated with a significant decrease in fat mass (Po0.05) with sparing of lean tissue. Plasma cholesterol, triglycerides and insulin were also significantly reduced (Po0.05). Exenatide at 10 mg/kg significantly reduced food intake (Po0.05) but failed to induce kaolin intake. In general, locomotor activity was reduced at doses of exenatide that decreased food intake, although a slightly higher dose was required to produce significant changes in activity. Conclusion: Systemic exenatide reduces body weight gain in normal, high-fat-fed rodents, a model that parallels human genetic variation and food consumption patterns, and may play a role in metabolic pathways mediating food intake.

The nucleus tractus solitarius: a portal for visceral afferent signal processing, energy status assessment and integration of their combined effects on food intake

“…The vagally transmitted effects of peripheral GLP-1R stimulation therefore involve behavioral and autonomic effector pathways that are downstream of CNS processing. [17][18][19]21,25 Structures in the ascending visceral afferent pathway, which includes nuclei of the caudal brainstem (NTS; parabrachial nucleus), hypothalamus (lateral hypothalamus; paraventricular nucleus) and basal forebrain (bed nucleus of stria terminalis; central nucleus of the amygdala), 26,27 may therefore play a role in mediating responses triggered by peripheral GLP-1R agonist treatmentA role. Similarly for the central GLP-1 system, direct central GLP-1R ligand administration activates neurons in many of the same central structures that show GLP-1-binding 23 and/or express GLP-1R mRNA.…”

Exogenous peptide YY3-36 and Exendin-4 further decrease food intake, whereas octreotide increases food intake in rats after Roux-en-Y gastric bypass

“…Post hoc Bonferroni test was used for time to time analysis between the two treatment groups (*Po0.05, **Po0.01, ***Po0.001). 21,24,25 and humans. 26,27 The novel finding of this study is that food intake after gastric bypass can be altered by pharmacological doses of gut hormones or gut hormone analogues.…”

Peroxisome proliferator-activated receptor-α activator fenofibrate prevents high-fat diet-induced renal lipotoxicity in spontaneously hypertensive rats

“…[35][36][37][38][39] In this study, we found excessive abnormal lipid accumulation in the renal tissue of SHR-HF animals compared with that in WKY-HF groups, which was related to increases in the mesangial matrix, TGF-b1 expression, apoptotic glomerular cells and the infiltration of inflammatory cells into kidneys. These findings are consistent with those of previous studies showing that lipid accumulation in kidneys promotes glomerulosclerosis through the low-density lipoprotein-receptor in mesangial cells, through macrophage chemotaxis, increased production of fibrotic cytokines and direct podocyte injury through oxidative stress.…”