Mitochondrial dysfunction has been associated to unbalanced energy intake and expenditure and has been proposed as a possible cause to the onset of obesity and the often consequent insulin resistance and diabetes. By using selective biochemical inhibitors here we show that class I histone deacetylases (HDACs) are important regulators of mitochondrial function. MS275, a class I selective HDAC inhibitor, increased mitochondrial biogenesis and oxidative metabolism in C2C12 murine myotubes via upregulation of the coactivator PGC-1 α, a key determinant of mitochondrial biogenesis. Knock down of HDAC3 by RNAi increased the expression of PGC-1 α and recapitulated the effects of MS275. Administration of MS275 to db/db mice improved the obese and diabetic phenotype as body weight, fasting glucose and insulin levels were lower and insulin sensitivity was higher than in control mice. Metabolic studies showed elevated oxygen consumption in mice on MS275 and the concomitant decrease of the respiratory exchange ratio suggested a switch to 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-1 α. Remarkably, visceral white adipose tissue (WAT) of mice treated with MS275 underwent a major reprogramming as several markers of brown fat were increased in a Prdm16-independent fashion. 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-1 α /Ppar γ axis in adipose tissue, leading to insulin sensitizing effect in db/db mice. Acknowledgment: funded by EU FP6 LSHM-CT 2006-037498, Cariplo Foundation 2008.2511, the Armenise Harvard Foundation and PRIN 2008 ZTN724.

Class I histone deacetylases and energy metabolism: new palyers in diabesity? / M. Crestani, A. Galmozzi, N. Mitro, A. Ferrari, E. Gers, F. Gilardi, G. Cermenati, D. Caruso, A. Mai, E. Saez, E. De Fabiani. - In: THE FEBS JOURNAL. - ISSN 1742-464X. - 278:suppl. 1(2011 Jun), pp. 177-177. ((Intervento presentato al 36. convegno FEBS congress, biochemistry for tomorrow's medicine tenutosi a Torino nel 2011 [10.1111/j.1742-4658.2011.08137.x].

Class I histone deacetylases and energy metabolism: new palyers in diabesity?

M. Crestani;A. Galmozzi;N. Mitro;E. Gers;F. Gilardi;G. Cermenati;D. Caruso;E. De Fabiani
2011-06

Abstract

Mitochondrial dysfunction has been associated to unbalanced energy intake and expenditure and has been proposed as a possible cause to the onset of obesity and the often consequent insulin resistance and diabetes. By using selective biochemical inhibitors here we show that class I histone deacetylases (HDACs) are important regulators of mitochondrial function. MS275, a class I selective HDAC inhibitor, increased mitochondrial biogenesis and oxidative metabolism in C2C12 murine myotubes via upregulation of the coactivator PGC-1 α, a key determinant of mitochondrial biogenesis. Knock down of HDAC3 by RNAi increased the expression of PGC-1 α and recapitulated the effects of MS275. Administration of MS275 to db/db mice improved the obese and diabetic phenotype as body weight, fasting glucose and insulin levels were lower and insulin sensitivity was higher than in control mice. Metabolic studies showed elevated oxygen consumption in mice on MS275 and the concomitant decrease of the respiratory exchange ratio suggested a switch to 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-1 α. Remarkably, visceral white adipose tissue (WAT) of mice treated with MS275 underwent a major reprogramming as several markers of brown fat were increased in a Prdm16-independent fashion. 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-1 α /Ppar γ axis in adipose tissue, leading to insulin sensitizing effect in db/db mice. Acknowledgment: funded by EU FP6 LSHM-CT 2006-037498, Cariplo Foundation 2008.2511, the Armenise Harvard Foundation and PRIN 2008 ZTN724.
Settore BIO/10 - Biochimica
THE FEBS JOURNAL
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/2434/166152
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