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

Many transcriptional and epigenetic mechanisms are involved in the regulation of lipid metabolism. Histone deacetylases 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. It has been shown that mitochondrial dysfunction associated to unbalanced energy intake and expenditure could be a possible cause to the onset of obesity and insulin resistance. By using selective biochemical inhibitors here we show that class I histone deacetylase (HDACs) are important regulators of mitochondrial lipid oxidation. MS272, a class I selective HDAC inhibitor, increased mitochondrial biogenesis and oxidative metabolism in C2C12 murine myotubes via upregulation of the transcriptional coactivator PGC-1a, a key determinant of mitochondrial biogenesis. Knock down of HDAC3 by RNAi increased the expression of PGC-1a and recapitulated the effects of MS275. Administration of MS275 to db/db mice improved the obese and diabetic phenotype, by reducing body weight, fasting glucose and insulin and by increasing insulin sensitivity. Metabolic studies showed elevated oxygen consumption in mice on MS275 and the concomitant decrease of the respiratory exchange ratio suggested a switch to lipid oxidative metabolism. In addition, higher heat production was noticed in mice treated with MS275, an effect paralleled by the improved functionality of brown adipose tissue consequent to increased expression of typical marker genes such as Ucp1, Prdm16, Adrb3, Pgc-1a. We also show that class I HDAC inhibitors cause a major reprogramming leading to a dramatic “browning” of white adipose tissue (WAT) in a Prdm16-independent fashion and promote lipid catabolism and mitochondrial biogenesis. At the same time, infiltration of macrophages and the expression of inflammatory markers in WAT were reduced. In conclusion, biochemical inhibition of class I HDACs revealed a mitochondrial signature mediated by the transcriptional coactivator Pgc-1a in skeletal muscle and by the Pgc-1a/Pparg axis in adipose tissue, leading to increased lipid oxidation and ultimately to insulin sensitizing effect in db/db mice. Acknowledgements: funded by EU FP6 LSHM-CT 2006-037498. Cariplo Foundation 2008.2511, the Armenise Harvard Foundation and PRIN 2008 ZTN724.