2. Academic Validation
  3. Nicotinamide N-methyltransferase knockdown protects against diet-induced obesity

Nicotinamide N-methyltransferase knockdown protects against diet-induced obesity

  • Nature. 2014 Apr 10;508(7495):258-62. doi: 10.1038/nature13198.
Daniel Kraus 1,  Qin Yang 1,  Dong Kong 2,  Alexander S Banks 3,  Lin Zhang 2,  Joseph T Rodgers 3,  Eija Pirinen 4,  Thomas C Pulinilkunnil 5,  Fengying Gong 5,  Ya-chin Wang 2,  Yana Cen 6,  Anthony A Sauve 6,  John M Asara 7,  Odile D Peroni 2,  Brett P Monia 8,  Sanjay Bhanot 8,  Leena Alhonen 4,  Pere Puigserver 3,  Barbara B Kahn 2
Affiliations

Affiliations

  • 1 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.).
  • 2 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.
  • 3 Department of Cancer Biology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115, USA.
  • 4 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.).
  • 5 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.).
  • 6 Department of Pharmacology, Weill Medical College of Cornell University, 1300 York Avenue, New York, New York 10065, USA.
  • 7 Division of Signal Transduction, Beth Israel Deaconess Medical Center and Harvard Medical School, 330 Brookline Ave, Boston, Massachusetts 02215, USA.
  • 8 Isis Pharmaceuticals, 1896 Rutherford Road, Carlsbad, California 92008-7326, USA.
PMID: 24717514 DOI: 10.1038/nature13198
Abstract

In obesity and type 2 diabetes, GLUT4 glucose 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 methyl donor. 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.

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