1] Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, 330 Brookline Avenue, Boston, Massachusetts 02215, USA [2] [3] Division of Nephrology, Department of Internal Medicine I, Würzburg University Hospital, Oberdürrbacher Straße 6, 97080 Würzburg, Germany (D.K.); Department of Medicine, Physiology and Biophysics, Center for Diabetes Research and Treatment, and Center for Epigenetics and Metabolism, University of California, Irvine, California 92697, USA (Q.Y.); Research Programs Unit, Molecular Neurology, Biomedicum Helsinki, University of Helsinki, 00290, Helsinki, Finland (E.P.); Department of Biochemistry and Molecular Biology, Faculty of Medicine, Dalhousie Medicine New Brunswick, Dalhousie University, Saint John, New Brunswick E2L4L5, USA (T.C.P.); Department of Endocrinology, Key Laboratory of Endocrinology of Ministry of Health, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China (F.G.); School of Pharmacy, University of Eastern Finland, P.O. Box 1627, FI-70211 Kuopio, Finland (L.A.).
Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, 330 Brookline Avenue, Boston, Massachusetts 02215, USA.
Department of Cancer Biology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115, USA.
1] Biotechnology and Molecular Medicine, A.I. Virtanen Institute for Molecular Sciences, Biocenter Kuopio, University of Eastern Finland, Kuopio Campus, PO Box 1627, FI-70211 Kuopio, Finland [2] Division of Nephrology, Department of Internal Medicine I, Würzburg University Hospital, Oberdürrbacher Straße 6, 97080 Würzburg, Germany (D.K.); Department of Medicine, Physiology and Biophysics, Center for Diabetes Research and Treatment, and Center for Epigenetics and Metabolism, University of California, Irvine, California 92697, USA (Q.Y.); Research Programs Unit, Molecular Neurology, Biomedicum Helsinki, University of Helsinki, 00290, Helsinki, Finland (E.P.); Department of Biochemistry and Molecular Biology, Faculty of Medicine, Dalhousie Medicine New Brunswick, Dalhousie University, Saint John, New Brunswick E2L4L5, USA (T.C.P.); Department of Endocrinology, Key Laboratory of Endocrinology of Ministry of Health, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China (F.G.); School of Pharmacy, University of Eastern Finland, P.O. Box 1627, FI-70211 Kuopio, Finland (L.A.).
1] Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, 330 Brookline Avenue, Boston, Massachusetts 02215, USA [2] Division of Nephrology, Department of Internal Medicine I, Würzburg University Hospital, Oberdürrbacher Straße 6, 97080 Würzburg, Germany (D.K.); Department of Medicine, Physiology and Biophysics, Center for Diabetes Research and Treatment, and Center for Epigenetics and Metabolism, University of California, Irvine, California 92697, USA (Q.Y.); Research Programs Unit, Molecular Neurology, Biomedicum Helsinki, University of Helsinki, 00290, Helsinki, Finland (E.P.); Department of Biochemistry and Molecular Biology, Faculty of Medicine, Dalhousie Medicine New Brunswick, Dalhousie University, Saint John, New Brunswick E2L4L5, USA (T.C.P.); Department of Endocrinology, Key Laboratory of Endocrinology of Ministry of Health, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China (F.G.); School of Pharmacy, University of Eastern Finland, P.O. Box 1627, FI-70211 Kuopio, Finland (L.A.).
Department of Pharmacology, Weill Medical College of Cornell University, 1300 York Avenue, New York, New York 10065, USA.
Division of Signal Transduction, Beth Israel Deaconess Medical Center and Harvard Medical School, 330 Brookline Ave, Boston, Massachusetts 02215, USA.
Isis Pharmaceuticals, 1896 Rutherford Road, Carlsbad, California 92008-7326, USA.
In obesity and type 2 diabetes, Glut4glucose transporter expression is decreased selectively in adipocytes. Adipose-specific knockout or overexpression of Glut4 alters systemic insulin sensitivity. Here we show, using DNA array analyses, that nicotinamide N-methyltransferase (Nnmt) is the most strongly reciprocally regulated gene when comparing gene expression in white adipose tissue (WAT) from adipose-specific Glut4-knockout or adipose-specific Glut4-overexpressing mice with their respective controls. NNMT methylates nicotinamide (vitamin B3) using S-adenosylmethionine (SAM) as a methyldonor. Nicotinamide is a precursor of NAD(+), an important cofactor linking cellular redox states with energy metabolism. SAM provides propylamine for polyamine biosynthesis and donates a methyl group for histone methylation. Polyamine flux including synthesis, catabolism and excretion, is controlled by the rate-limiting enzymes ornithine decarboxylase (ODC) and spermidine-spermine N(1)-acetyltransferase (SSAT; encoded by Sat1) and by polyamine oxidase (PAO), and has a major role in energy metabolism. We report that NNMT expression is increased in WAT and liver of obese and diabetic mice. Nnmt knockdown in WAT and liver protects against diet-induced obesity by augmenting cellular energy expenditure. NNMT inhibition increases adipose SAM and NAD(+) levels and upregulates ODC and SSAT activity as well as expression, owing to the effects of NNMT on histone H3 lysine 4 methylation in adipose tissue. Direct evidence for increased polyamine flux resulting from NNMT inhibition includes elevated urinary excretion and adipocyte secretion of diacetylspermine, a product of polyamine metabolism. NNMT inhibition in adipocytes increases oxygen consumption in an ODC-, SSAT- and PAO-dependent manner. Thus, NNMT is a novel regulator of histone methylation, polyamine flux and NAD(+)-dependent SIRT1 signalling, and is a unique and attractive target for treating obesity and type 2 diabetes.
