Inhibition of class I histone deacetylases unveils a mitochondrial signature and enhances lipid oxidation in skeletal muscle and adipose tissue

Histone deacetylases (HDACs) and nuclear receptors play an important role in the regulation of lipid metabolism in adipose tissues, liver and skeletal muscles in normal and disease states. Unbalanced energy intake and expenditure resulting from mitochondrial dysfunction have been shown to contribute to the onset of obesity and insulin resistance. By using different in vitro and in vivo approaches here we show that class I HDAC are important regulators of mitochondrial lipid oxidation. MS275, a class I selective HDAC inhibitor, increased mitochondrial biogenesis and oxidative metabolism in C2C12 murine myotubes via upregulation of the coactivator PGC-1α. Knock down of Hdac3 by RNAi recapitulated the effects of MS275. Administration of MS275 to db/db mice improved the obese and diabetic phenotype, by reducing bodyweight, fasting circulating glucose and insulin. Metabolic studies showed elevated oxygen consumption and a switch to lipid oxidative metabolism in mice on MS275 as suggested by reduction of the respiratory exchange ratio. In addition, higher heat production and improved functionality of brown adipose tissue consequent to increased expression to increased expression of Ucp1, Prdm16, Adrb3, Pgc-1α were noticed in mice treated with MS275. We also show that the class I HDAC inhibitor caused a dramatic “browning” of white adipose tissue in a Prdm16-independent fashion and promoted mitochondrial oxidative metabolism via upregulation of Pgc-1α and Pparγ. In conclusion, inhibition of class I HDACs revealed a mitochondrial signature mediated by Pgc-1α in skeletal muscle and by the Pgc-1α/Pparγ axis in adipose tissue, leading to increased lipid oxidation and ultimately to insulin sensitizing effect in diabetic mice. (Funded by EU FP6 LSHM-CT2006-037498, Cariplo Foundation 2008.2511, The Armenise-Harvad Foundation and PRIN 2008 ZTN724)