Publication Date:
2014-04-11
Description:
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.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4107212/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉 〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4107212/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Kraus, Daniel -- Yang, Qin -- Kong, Dong -- Banks, Alexander S -- Zhang, Lin -- Rodgers, Joseph T -- Pirinen, Eija -- Pulinilkunnil, Thomas C -- Gong, Fengying -- Wang, Ya-chin -- Cen, Yana -- Sauve, Anthony A -- Asara, John M -- Peroni, Odile D -- Monia, Brett P -- Bhanot, Sanjay -- Alhonen, Leena -- Puigserver, Pere -- Kahn, Barbara B -- K01 DK094943/DK/NIDDK NIH HHS/ -- K08 DK090149/DK/NIDDK NIH HHS/ -- P01 CA120964/CA/NCI NIH HHS/ -- P01CA120964/CA/NCI NIH HHS/ -- P30 DK040561/DK/NIDDK NIH HHS/ -- P30 DK0460200/DK/NIDDK NIH HHS/ -- P30 DK046200/DK/NIDDK NIH HHS/ -- P30 DK057521/DK/NIDDK NIH HHS/ -- P30 DK57521/DK/NIDDK NIH HHS/ -- P30CA006516-46/CA/NCI NIH HHS/ -- R01 DK069966/DK/NIDDK NIH HHS/ -- R01 DK100385/DK/NIDDK NIH HHS/ -- R01 DK69966/DK/NIDDK NIH HHS/ -- R37 DK043051/DK/NIDDK NIH HHS/ -- R37 DK43051/DK/NIDDK NIH HHS/ -- England -- Nature. 2014 Apr 10;508(7495):258-62. doi: 10.1038/nature13198.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉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, Wurzburg University Hospital, Oberdurrbacher Strasse 6, 97080 Wurzburg, 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, Wurzburg University Hospital, Oberdurrbacher Strasse 6, 97080 Wurzburg, 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, Wurzburg University Hospital, Oberdurrbacher Strasse 6, 97080 Wurzburg, 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.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24717514" target="_blank"〉PubMed〈/a〉
Keywords:
Acetyltransferases/metabolism
;
Adipocytes/metabolism/secretion
;
Adipose Tissue/enzymology/metabolism
;
Adipose Tissue, White/enzymology/metabolism
;
Animals
;
Diabetes Mellitus, Type 2/enzymology/metabolism
;
*Diet
;
Energy Metabolism
;
Fatty Liver
;
Gene Knockdown Techniques
;
Glucose Intolerance
;
Glucose Transporter Type 4/deficiency/genetics/metabolism
;
Insulin Resistance
;
Liver/enzymology
;
Male
;
Mice
;
Mice, Inbred C57BL
;
NAD/metabolism
;
Niacinamide/metabolism
;
Nicotinamide N-Methyltransferase/*deficiency/genetics/*metabolism
;
Obesity/*enzymology/etiology/genetics/*prevention & control
;
Ornithine Decarboxylase/metabolism
;
Oxidoreductases Acting on CH-NH Group Donors/metabolism
;
S-Adenosylmethionine/metabolism
;
Sirtuin 1/metabolism
;
Spermine/analogs & derivatives/metabolism
;
Thinness/enzymology/metabolism
Print ISSN:
0028-0836
Electronic ISSN:
1476-4687
Topics:
Biology
,
Chemistry and Pharmacology
,
Medicine
,
Natural Sciences in General
,
Physics
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