Role of the receptor GPR109a in the effects of tributyrin in mice fed high-fat diet

Abstract

Butyrate is a short chain fatty acid (SCFA) produced by components of the intestinal microbiota. Elevation in its availability by fiber intake or diet supplementation has been shown to prevent the development of metabolic disarrangements and the insulin resistance associated with obesity. Tributyrin (Tb) is a pro-drug of butyrate. This triglyceride, which contains three butyrate moieties, it is rapidly hydrolyzed after oral administration releasing butyrate in the blood circulation. The aim of this study is to investigate the participation of the receptor GPR109A, a membrane protein that can be activated by agonists including hydroxybutyrate, nicotinic acid and butyrate, in the effects of tributyrin in a murine model of obesity and insulin resistance. GPR109A knockout and wild type mice will be fed with a high-fat diet for 8 weeks and then treated by gavage with Tb (2 g/kg bw, 3 times a week) during 6 weeks. Mice will be evaluated for glucose and insulin tolerance one week before the beggining of the treatment and four weeks after Tb administration started. At the end of the treatment mice will be killed and biological samples including liver, serum and adipose tissue will be collected. The serum will be used for determination of lipids profile (cholesterol, triglycerides and non sterefied fatty acids measurement) and the activity of hepatic enzymes. The liver will be used for triglycerides measurement and histologycal analysis. Adipose tissue will be digested with collagenase for obtention of adipocytes and stromal cells. Lipolysis will be measured in the adipocytes, while in the stromal fraction, the amount of M1 and M2 macrophages will be analysed by flow cytometry.