Rationale: Obesity is a multifactor metabolic disorder with increased prevalence worldwide. Pharmacological treatment has not yet met the safety, efficacy and sustainable maintenance of weight loss. Recent studies demonstrate that the combined activation of GPR40 and GPR120 may contribute to the treatment of obesity, since POMC neurons (which provide anorexigenic signals in the hypothalamus) express GLP-1 and GPR40 receptor and that GPR120 is expressed in microglia. Using high affinity ligands and selectivity allows one to explore pharmacological functions and develop potential therapeutic targets.Objective: To evaluate the effect of the combination of GPR40 and GPR120 agonists (single or double) with GLP-1 agonist for the treatment of experimental obesity.Materials and methods: Swiss male mice, on a hyperlipidic diet for 8 weeks, will receive vehicle; GLP-1 agonist alone or with GPR40 agonist and GPR120 (single or double agonist) via intracerebroventricular (ICV) for 14 days. Food intake; weight evolution; determination of adipose mass; gene expression of POMC neurons and inflammatory cytokines; glucose, insulin and leptin tolerance tests; respirometry; and stool composition will be evaluated. Values expressed as mean ± standard deviation will be analyzed by T-test (2 groups) or analysis of variance (One-wayANOVA) with a test of significance (Bonferroni test), comparing experimental groups. The level of significance will be p <0.05.Prospects: The combination of the three agonists (GLP-1, GPR40 and GPR120) may have a long-term positive effect on obesity, reducing dietary intake and inflammation induced by diet.
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