EPIGENETICS OF ENERGY METABOLISM: FOCUS ON CLASS I HISTONE DEACETYLASES

Enviromental and nutritional stimuli can affect chromatin modifications. Several evidences highlighted the role of epigenetics in the regulation of energy homeostasis. Among the epigenetic modifications, the acetylation/deacetylation of histone tails it has been associated to metabolic disorders such as obesity and diabetes that are often linked with defects in oxidative metabolism. In this doctorate thesis it has been investigated the effect of the selective inhibition of class I histone deacetylases (HDACs) in metabolic profile and functionality of key organs participating in energy metabolism. Cultured myotubes and primary brown adipocytes treated with a class I-specific HDAC inhibitor showed higher expression of Pgc-1α, increased mitochondrial biogenesis, and augmented oxygen consumption. In vitro and in vivo ChIP experiments suggested that these beneficial effects are mediated by inhibition of HDAC3. Treatment of diet induced obese mice with a class I-selective HDAC inhibitor MS275 reduced body weight and improved glucose tolerance. Moreover inhibition of class I HDACs increased thermogenic capacity and brown adipose tissue (BAT) functionality, reduced abdominal fat and decreased size of subcutaneous and visceral adipocytes. Visceral and subcutaneous white adipose tissues from these mice showed higher expression of functionality markers, along with enhanced oxidative metabolism. Interestingly in this mouse model MS275 was able to induce browning of visceral white adipose tissue. In vitro experiments indicated that early inhibition of class I HDACs in adipose precursors reprograms cell fate of adipose precursors toward an oxidative and more functional adipose phenotype.