Pharmacological stimulation of NADH oxidation ameliorates obesity and related phenotypes in mice

Diabetes. 2009 Apr;58(4):965-74. doi: 10.2337/db08-1183. Epub 2009 Jan 9.

Abstract

Objective: Nicotinamide adenine dinucleotides (NAD+ and NADH) play a crucial role in cellular energy metabolism, and a dysregulated NAD+-to-NADH ratio is implicated in metabolic syndrome. However, it is still unknown whether a modulating intracellular NAD+-to-NADH ratio is beneficial in treating metabolic syndrome. We tried to determine whether pharmacological stimulation of NADH oxidation provides therapeutic effects in rodent models of metabolic syndrome.

Research design and methods: We used beta-lapachone (betaL), a natural substrate of NADH:quinone oxidoreductase 1 (NQO1), to stimulate NADH oxidation. The betaL-induced pharmacological effect on cellular energy metabolism was evaluated in cells derived from NQO1-deficient mice. In vivo therapeutic effects of betaL on metabolic syndrome were examined in diet-induced obesity (DIO) and ob/ob mice.

Results: NQO1-dependent NADH oxidation by betaL strongly provoked mitochondrial fatty acid oxidation in vitro and in vivo. These effects were accompanied by activation of AMP-activated protein kinase and carnitine palmitoyltransferase and suppression of acetyl-coenzyme A (CoA) carboxylase activity. Consistently, systemic betaL administration in rodent models of metabolic syndrome dramatically ameliorated their key symptoms such as increased adiposity, glucose intolerance, dyslipidemia, and fatty liver. The treated mice also showed higher expressions of the genes related to mitochondrial energy metabolism (PPARgamma coactivator-1alpha, nuclear respiratory factor-1) and caloric restriction (Sirt1) consistent with the increased mitochondrial biogenesis and energy expenditure.

Conclusions: Pharmacological activation of NADH oxidation by NQO1 resolves obesity and related phenotypes in mice, opening the possibility that it may provide the basis for a new therapy for the treatment of metabolic syndrome.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenylate Kinase / metabolism
  • Animals
  • Disease Models, Animal
  • Energy Metabolism / drug effects
  • Metabolic Syndrome / drug therapy
  • Mice
  • Mice, Knockout
  • NAD / metabolism*
  • NAD(P)H Dehydrogenase (Quinone)
  • NADPH Dehydrogenase / deficiency
  • NADPH Dehydrogenase / genetics
  • NADPH Dehydrogenase / metabolism
  • Naphthoquinones / therapeutic use*
  • Obesity / drug therapy*
  • Obesity / genetics*
  • Oxidation-Reduction
  • Phenotype
  • Signal Transduction / physiology

Substances

  • Naphthoquinones
  • NAD
  • beta-lapachone
  • NAD(P)H Dehydrogenase (Quinone)
  • Nqo1 protein, mouse
  • NADPH Dehydrogenase
  • Adenylate Kinase