Evidence map›Paper›PMID 24717514›Full record

ArticleNature2014

Nicotinamide N-methyltransferase knockdown protects against diet-induced obesity.

Daniel Kraus, Qin Yang, Dong Kong, Alexander S Banks, Lin Zhang, Joseph T Rodgers, Eija Pirinen, Thomas C Pulinilkunnil, Fengying Gong, Ya-chin Wang and 9 more

Open access · bronzeAbstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Nature, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 282 papers, 3 of them syntheses that pooled it.

0numbers the graph read from it
0cells of the map it votes in
282citing papers in PubMed, 3 pooled it
22.1field-weighted citation impact, top 1% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

282 citing papers in PubMed, 3 syntheses or guidelines pooled it, 488 citations in OpenAlex.

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222 more citing papers are in PubMed but not listed here.

4 · The record

Corrections and comments

5 · Who and what money

Authors and funding

19 authors at 6 institutions in 3 countries.

Daniel Kraus1] 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 Yang1] 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.).
Dong KongDivision of Endocrinology, Diabetes, and Metabolism, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, 330 Brookline Avenue, Boston, Massachusetts 02215, USA.
Alexander S BanksDepartment of Cancer Biology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115, USA.
Lin ZhangDivision of Endocrinology, Diabetes, and Metabolism, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, 330 Brookline Avenue, Boston, Massachusetts 02215, USA.
Joseph T RodgersDepartment of Cancer Biology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115, USA.
Eija Pirinen1] 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.).
Thomas C Pulinilkunnil1] 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 Gong1] 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.).
Ya-chin WangDivision of Endocrinology, Diabetes, and Metabolism, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, 330 Brookline Avenue, Boston, Massachusetts 02215, USA.
Yana CenDepartment of Pharmacology, Weill Medical College of Cornell University, 1300 York Avenue, New York, New York 10065, USA.
Anthony A SauveDepartment of Pharmacology, Weill Medical College of Cornell University, 1300 York Avenue, New York, New York 10065, USA.
John M AsaraDivision of Signal Transduction, Beth Israel Deaconess Medical Center and Harvard Medical School, 330 Brookline Ave, Boston, Massachusetts 02215, USA.
Odile D PeroniDivision of Endocrinology, Diabetes, and Metabolism, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, 330 Brookline Avenue, Boston, Massachusetts 02215, USA.
Brett P MoniaIsis Pharmaceuticals, 1896 Rutherford Road, Carlsbad, California 92008-7326, USA.
Sanjay BhanotIsis Pharmaceuticals, 1896 Rutherford Road, Carlsbad, California 92008-7326, USA.
Leena Alhonen1] 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.).
Pere PuigserverDepartment of Cancer Biology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115, USA.
Barbara B KahnDivision of Endocrinology, Diabetes, and Metabolism, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, 330 Brookline Avenue, Boston, Massachusetts 02215, USA.
Beth Israel Deaconess Medical Center · USHarvard University · USDana-Farber Cancer Institute · USCornell University · USIonis Pharmaceuticals (United States) · USUniversity of Eastern Finland · FI

Funding

VectorP30CA006516 · NCI · DANA-FARBER CANCER INSTITUTE · PI A. Heather Eliassen · 1985 to 2026
$330.6M
Tuberous Sclerosis-Pathway and PathogenesisP01CA120964 · NCI · BRIGHAM AND WOMEN'S HOSPITAL · PI David J. Kwiatkowski · 2007 to 2026
$35.9M
ROLE OF DIETARY CONSTITUENTS ON GENE EXPRESSION IN INTESTINAL EPITHELIUMP30DK040561 · NIDDK · MASSACHUSETTS GENERAL HOSPITAL · PI CHRISTOPHER P DUGGAN · 1994 to 2026
$31.6M
Transgenic CoreP30DK057521 · NIDDK · MASSACHUSETTS GENERAL HOSPITAL · PI FLOREZ, JOSE CARLOS · 2000 to 2019
$31.4M
Transgenic CoreP30DK046200 · NIDDK · TUFTS MEDICAL CENTER · PI GREENBERG, ANDREW S, PERISSI, VALENTINA · 1992 to 2021
$25.0M
INTEGRATED ENDOCRINE &METABOLIC RESEARCH TRAININGT32DK007516 · NIDDK · BETH ISRAEL DEACONESS MEDICAL CENTER · PI BARBARA B. KAHN · 1986 to 2026
$6.8M
Glucose Transporter Regulation in Obesity and DiabetesR37DK043051 · NIDDK · BETH ISRAEL DEACONESS MEDICAL CENTER · PI KAHN, BARBARA B. · 2006 to 2015
$5.0M
GLUCOSE TRANSPORTER REGULATION IN OBESITY AND DIABETESR01DK043051 · NIDDK · BETH ISRAEL DEACONESS MEDICAL CENTER · PI KAHN, BARBARA B. · 1992 to 2020
$4.4M
Control of Nutrient Homeostasis through PGC-1alpha and SIRT1R01DK069966 · NIDDK · JOHNS HOPKINS UNIVERSITY · PI PUIGSERVER, PERE · 2005 to 2014
$4.2M
Nicotinamide N-methyltransferase is a novel regulator of energy expenditureR01DK100385 · NIDDK · UNIVERSITY OF CALIFORNIA-IRVINE · PI YANG, QIN · 2014 to 2018
$1.7M
Dendritic Spines on AgRP Neurons as Communication Hubs Controlling FeedingK01DK094943 · NIDDK · TUFTS UNIVERSITY BOSTON · PI KONG, DONG · 2013 to 2015
$456k
Nicotinamide N-methyltransferase (NNMT) in obesity and insulin resistanceK08DK090149 · NIDDK · BETH ISRAEL DEACONESS MEDICAL CENTER · PI YANG, QIN · 2011 to 2013
$452k
American Heart Association-American Stroke Association 13SDG14620005NCI NIH HHS P01 CA120964NCI NIH HHS P01CA120964NCI NIH HHS P30 CA006516NCI NIH HHS P30CA006516-46NIDDK NIH HHS K01 DK094943NIDDK NIH HHS K08 DK090149NIDDK NIH HHS P30 DK040561NIDDK NIH HHS P30 DK0460200NIDDK NIH HHS P30 DK046200NIDDK NIH HHS P30 DK057521NIDDK NIH HHS P30 DK57521NIDDK NIH HHS R01 DK043051NIDDK NIH HHS R01 DK069966NIDDK NIH HHS R01 DK100385NIDDK NIH HHS R01 DK69966NIDDK NIH HHS R37 DK043051NIDDK NIH HHS R37 DK43051NIDDK NIH HHS T32 DK007516
6 · The paper itself

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.

Indexed as

DietAcetyltransferasesAdipocytesAdipose TissueAdipose Tissue, WhiteAnimalsDiabetes Mellitus, Type 2Diamine N-AcetyltransferaseEnergy MetabolismFatty LiverGene Knockdown TechniquesGlucose IntoleranceGlucose Transporter Type 4Insulin ResistanceLiverMaleAcetyltransferasesDiamine N-AcetyltransferaseGlucose Transporter Type 4NADNiacinamideNicotinamide N-MethyltransferaseN',N''-diacetylspermineOrnithine DecarboxylaseOxidoreductases Acting on CH-NH Group DonorsPolyamine OxidaseS-AdenosylmethionineSirt1 protein, mouseSirtuin 1Spermine

Identifiers

PMID24717514
PMCPMC4107212
OpenAlexW2062481845

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.