Nicotinamide N-methyltransferase knockdown protects against diet-induced obesity.
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.
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.).
Daniel
D
Kraus
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.).
Qin
Q
Yang
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.
Dong
D
Kong
Department of Cancer Biology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115, USA.
Alexander S
AS
Banks
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.
Lin
L
Zhang
Department of Cancer Biology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115, USA.
Joseph T
JT
Rodgers
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.).
Eija
E
Pirinen
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.).
Thomas C
TC
Pulinilkunnil
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.).
Fengying
F
Gong
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.
Ya-chin
YC
Wang
Department of Pharmacology, Weill Medical College of Cornell University, 1300 York Avenue, New York, New York 10065, USA.
Yana
Y
Cen
Department of Pharmacology, Weill Medical College of Cornell University, 1300 York Avenue, New York, New York 10065, USA.
Anthony A
AA
Sauve
Division of Signal Transduction, Beth Israel Deaconess Medical Center and Harvard Medical School, 330 Brookline Ave, Boston, Massachusetts 02215, USA.
John M
JM
Asara
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.
Odile D
OD
Peroni
Isis Pharmaceuticals, 1896 Rutherford Road, Carlsbad, California 92008-7326, USA.
Brett P
BP
Monia
Isis Pharmaceuticals, 1896 Rutherford Road, Carlsbad, California 92008-7326, USA.
Sanjay
S
Bhanot
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.).
Leena
L
Alhonen
Department of Cancer Biology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115, USA.
Pere
P
Puigserver
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.
Barbara B
BB
Kahn
D000123:Acetyltransferases / Q000378:metabolism; D017667:Adipocytes / Q000378:metabolism; D000273:Adipose Tissue / Q000201:enzymology / Q000378:metabolism; D052436:Adipose Tissue, White / Q000201:enzymology / Q000378:metabolism; D000818:Animals; D003924:Diabetes Mellitus, Type 2 / Q000201:enzymology / Q000378:metabolism; D004032:Diet; D004734:Energy Metabolism; D005234:Fatty Liver; D055785:Gene Knockdown Techniques; D018149:Glucose Intolerance; D051275:Glucose Transporter Type 4 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D007333:Insulin Resistance; D008099:Liver / Q000201:enzymology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009243:NAD / Q000378:metabolism; D009536:Niacinamide / Q000378:metabolism; D050903:Nicotinamide N-Methyltransferase / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism*; D009765:Obesity / Q000201:enzymology* / Q000209:etiology / Q000235:genetics / Q000517:prevention & control*; D009955:Ornithine Decarboxylase / Q000378:metabolism; D000587:Oxidoreductases Acting on CH-NH Group Donors / Q000378:metabolism; D012436:S-Adenosylmethionine / Q000378:metabolism; D056564:Sirtuin 1 / Q000378:metabolism; D013096:Spermine / Q000031:analogs & derivatives / Q000378:metabolism; D013851:Thinness / Q000201:enzymology / Q000378:metabolism; D000097667:Polyamine Oxidase; D000099228:Diamine N-Acetyltransferase
D000123:Acetyltransferases; D051275:Glucose Transporter Type 4; D009243:NAD; D009536:Niacinamide; D050903:Nicotinamide N-Methyltransferase; D009955:Ornithine Decarboxylase; D000587:Oxidoreductases Acting on CH-NH Group Donors; D012436:S-Adenosylmethionine; D056564:Sirtuin 1; D013096:Spermine; D000097667:Polyamine Oxidase; D000099228:Diamine N-Acetyltransferase; C029453:N',N''-diacetylspermine; C470545:Sirt1 protein, mouse