Keeping fat out of muscle - Role of Branched Amino AcidsAmino Acids in Insulin Resistance

Abstract Type 2 Diabetes Mellitus (T2DM) and insulin resistance (IR) are major contributors to global cardiovascular morbidity and mortality. The parent R01 grant uncovered that branched-chain amino acid (BCAA) catabolism promotes glucose disposal through vascular smooth muscle cell (VSMC) relaxation. However, the molecular signaling pathways linking BCAA metabolism to vasodilation remain unclear. Recent evidence shows that BCAA-derived metabolites modulate histone acetylation, an epigenetic mechanism that enhances the expression of VSMC relaxation genes. Isoleucine provides carbon sources for histone acetylation marks, promoting a pro-relaxant VSMC phenotype, while isoleucine withdrawal reduces these marks, impairing vascular function. This suggests that histone acetylation mediates BCAA-driven vascular effects and systemic insulin sensitivity. This supplement investigates whether BCAA catabolism promotes VSMC relaxation and glucose disposal by enhancing histone acetylation at pro-relaxation gene loci. Our aims are: Aim 1: Test the hypothesis that BCAA catabolism promotes transcription of genes that enhance VSMC relaxation via histone acetylation. Aim 2: Assess whether histone acetylation drives VSMC relaxation and improves glucose disposal. Using in vivo histone acetyltransferase and deacetylase inhibitors, we will test the impact of histone acetylation on vascular tone and insulin sensitivity. This research could identify new epigenetic targets for enhancing vascular function and insulin sensitivity, leading to novel therapies for T2DM and cardiovascular disease. Additionally, it provides crucial training for our physician-scientist candidate, preparing him for a career in translational diabetes research.