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Effects of conditional deletion of free fatty acid receptor 1 (FFAR1) in POMC neurons on energy homeostasis

Grant number: 17/14963-6
Support type:Scholarships abroad - Research Internship - Post-doctor
Effective date (Start): November 01, 2017
Effective date (End): October 31, 2018
Field of knowledge:Biological Sciences - Physiology
Principal Investigator:Licio Augusto Velloso
Grantee:Nathalia Romanelli Vicente Dragano
Supervisor abroad: Miguel Lopez
Home Institution: Faculdade de Ciências Médicas (FCM). Universidade Estadual de Campinas (UNICAMP). Campinas , SP, Brazil
Local de pesquisa : Universidade de Santiago de Compostela, Santiago (USC), Spain  
Associated to the scholarship:14/26942-5 - Evaluation of intracerebroventricular treatment effect with selective agonists of GPR120 and GPR40 receptors and in high fat diet induced-obesity mice, BP.PD

Abstract

In the last few years, several studies have uncovered some molecular mechanisms in which omega-3 PUFA protect against obesity-related disorders. Studies have identified the PUFA receptors FFAR1/GPR40 and FFAR4/FGPR120 as attractive potential pharmacological targets. The activation of FFAR4/FGPR120 by PUFAs or synthetic ligands engages an atypical signaling system that attenuates metabolic inflammation in obesity. In addition, a number of studies have reported the potential benefits of systemically targeting GPR40 in type 2 diabeteS.Until recently, the impact of activation of hypothalamic FFAR1/GPR40 and FFAR4/FGPR120 as potential targets for the treatment of obesity was unknown. In a recent study, we showed that both receptors are expressed in the hypothalamus; GPR120 is primarily present in microglia, whereas GPR40 is expressed in neurons. Upon intracerebroventricular (icv) treatment, GW9508, a non-specific agonist for both receptors, reduced energy efficiency and the expression of inflammatory genes in the hypothalamus of obese mice. Moreover, obese mice showed interesting outcomes once treated icv with the GPR120- and GPR40-specific agonists TUG1197 and TUG905, respectively. TUG1197 treatment induced anti-inflammatory activity in the hypothalamus while TUG905 acted predominantly reducing body mass and increasing the expression of the POMC [25]. Therefore, these data suggest that FFAR1/GPR40 in POMC neurons constitute a key target governing energy balance and glucose homeostasis. First, POMC neurons in the ARC express FFAR1/GPR40 receptor. FFAR1/GPR40 agonists also stimulate POMC expression in the ARC. With these concepts in mind, the present research proposal plans to study FFAR1 function specifically in POMC neurons of mice. In this project we will generate mice by breeding the FFAR1 floxed mouse line with the Pomc-Cre mouse, resulting in a conditional and specific deletion of the FFAR1 allele in Pomc neurons. Once the transgenic mice are generated we plan to evaluate the metabolic phenotype of mice fed on chow and a high-fat diet. (AU)