Application of histone deacetylase inhibitors in the treatment of obesity and associated insulin resistance

Abstract

Obesity is a condition in which there is an excessive accumulation of adipose tissue. In Brazil, around 49% of the population is overweight, and 16% is obese. Obesity is associated with other diseases including diabetes mellitus type 2 (DM2), heart disease, hypertension, dyslipidemia and certain types of cancer, being considered a serious public health problem. Obesity is characterized by a chronic subclinical state of inflammation, which is involved in organ dysfunction. In this project, we aim to investigate the effect of histone deacetylase inhibitor (iHDAC), SAHA, and the prodrug of butyrate (tributyrin), which have significant anti-inflammatory effects, on the development of insulin resistance in a murine model of obesity. For this, C57BL/6 male adults mice will receive treatment with iHDAC for a period of 10 weeks concomitant with high fat diet. At the end of the protocol, insulin response (glucose metabolism and signaling to the hormone), lipid parameters (cholesterol, lipoproteins and free fatty acid concentrations), production of inflammatory mediators by peritoneal macrophages and white adipose tissue and activation of inflammatory pathways and insulin signaling in the liver, skeletal muscle and white adipose tissue will be determined. This protocol will also be applied to Ob/ob mice (leptin deficient), which develop obesity and insulin resistance. This project is important not only for understanding the mechanisms involved in the pathophysiology of insulin resistance, but also to investigate a possible preventive intervention and/or therapy for this pathological condition.