Nicotinamide N-methyltransferase knockdown protects against diet-induced obesity

Nature. 2014 Apr 10;508(7495):258-62. 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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetyltransferases / metabolism
  • Adipocytes / metabolism
  • Adipose Tissue / enzymology
  • Adipose Tissue / metabolism
  • Adipose Tissue, White / enzymology
  • Adipose Tissue, White / metabolism
  • Animals
  • Diabetes Mellitus, Type 2 / enzymology
  • Diabetes Mellitus, Type 2 / metabolism
  • Diet*
  • Energy Metabolism
  • Fatty Liver
  • Gene Knockdown Techniques
  • Glucose Intolerance
  • Glucose Transporter Type 4 / deficiency
  • Glucose Transporter Type 4 / genetics
  • Glucose Transporter Type 4 / metabolism
  • Insulin Resistance
  • Liver / enzymology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • NAD / metabolism
  • Niacinamide / metabolism
  • Nicotinamide N-Methyltransferase / deficiency*
  • Nicotinamide N-Methyltransferase / genetics
  • Nicotinamide N-Methyltransferase / metabolism*
  • Obesity / enzymology*
  • Obesity / etiology
  • Obesity / genetics
  • Obesity / prevention & control*
  • Ornithine Decarboxylase / metabolism
  • Oxidoreductases Acting on CH-NH Group Donors / metabolism
  • S-Adenosylmethionine / metabolism
  • Sirtuin 1 / metabolism
  • Spermine / analogs & derivatives
  • Spermine / metabolism
  • Thinness / enzymology
  • Thinness / metabolism

Substances

  • Glucose Transporter Type 4
  • NAD
  • Niacinamide
  • Spermine
  • N',N''-diacetylspermine
  • S-Adenosylmethionine
  • Oxidoreductases Acting on CH-NH Group Donors
  • polyamine oxidase
  • Nicotinamide N-Methyltransferase
  • Acetyltransferases
  • diamine N-acetyltransferase
  • Sirt1 protein, mouse
  • Sirtuin 1
  • Ornithine Decarboxylase

Associated data

  • GEO/GSE35378