PS-B11-1: ACETATE RESTORES CARDIAC METABOLIC FLEXIBILITY IN HIGH FAT DIET-INDUCED OBESITY THROUGH HDAC MODULATION

Abstract

Objectives: Obesity remains a global epidemic and an independent risk factor for cardiovascular disease. Histone deacetylase (HDAC) activity has been implicated to increase adipogenic differentiation and consequent increase in adiposity, which are crucial features of obesity. Short chain fatty acids (SCFAs), which are potential HDAC inhibitors have been shown to be effective for glycemic/immune modulation. However, the involvement of HDAC or ANP/BNP in obesity-associated cardiac metabolic events is inconclusive. The present study hypothesized that cardiac metabolic inflexibility is dependent on cardiac ANP/BNP alteration and HDAC activity. We further sought to investigate the therapeutic potential of SCFA, acetate in high fat diet (HFD)-induced obese rat model. Methods: Adult male Wistar rats were assigned into groups (n = 6/group): Control, Obese, Sodium acetate (NaAc)-treated and Obese+ NaAc-treated groups received distilled water once daily (oral gavage), 40% HFD ad libitum, 200 mg/kg NaAc once daily (oral gavage) and 40% HFD+NaAc respectively. Results: The treatments lasted for 12 weeks. HFD resulted in increased food intake, body weight and cardiac mass. It also caused insulin resistance and enhanced Beta-cell function, increased fasting insulin, lactate, plasma and cardiac triglyceride, total cholesterol, glycogen content, lipid peroxidation, TNF-alpha, IL-6, HDAC and cardiac troponin T and gamma-glutamyl transferase and decreased plasma and cardiac GSH with unaltered cardiac ANP and BNP. However, these alterations were averted when treated with acetate. Conclusions: Taken together, these results indicate that obesity induces defective cardiac metabolic flexibility, which is accompanied by elevated level of HDAC and not ANP/BNP alteration. The results also suggest that acetate ameliorates obesity-induced cardiac metabolic inflexibility by suppression of HDAC and independent of ANP/BNP modulation.