title: Pharmacological stimulation of NADH oxidation ameliorates obesity and related phenotypes in mice.
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.
  
  
  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.
authors.affiliation: Department of Internal Medicine, Chungnam National University School of Medicine, Daejeon, Korea.
authors.forename: Jung Hwan
authors.initials: JH
authors.lastname: Hwang
authors.forename: Dong Wook
authors.initials: DW
authors.lastname: Kim
authors.forename: Eun Jin
authors.initials: EJ
authors.lastname: Jo
authors.forename: Yong Kyung
authors.initials: YK
authors.lastname: Kim
authors.forename: Young Suk
authors.initials: YS
authors.lastname: Jo
authors.forename: Ji Hoon
authors.initials: JH
authors.lastname: Park
authors.forename: Sang Ku
authors.initials: SK
authors.lastname: Yoo
authors.forename: Myung Kyu
authors.initials: MK
authors.lastname: Park
authors.forename: Tae Hwan
authors.initials: TH
authors.lastname: Kwak
authors.forename: Young Lim
authors.initials: YL
authors.lastname: Kho
authors.forename: Jin
authors.initials: J
authors.lastname: Han
authors.forename: Hueng-Sik
authors.initials: HS
authors.lastname: Choi
authors.forename: Sang-Hee
authors.initials: SH
authors.lastname: Lee
authors.forename: Jin Man
authors.initials: JM
authors.lastname: Kim
authors.forename: InKyu
authors.initials: I
authors.lastname: Lee
authors.forename: Taeyoon
authors.initials: T
authors.lastname: Kyung
authors.forename: Cholsoon
authors.initials: C
authors.lastname: Jang
authors.forename: Jongkyeong
authors.initials: J
authors.lastname: Chung
authors.forename: Gi Ryang
authors.initials: GR
authors.lastname: Kweon
authors.forename: Minho
authors.initials: M
authors.lastname: Shong
mesh_terms: D000263:Adenylate Kinase / Q000378:metabolism; D000818:Animals; D004195:Disease Models, Animal; D004734:Energy Metabolism / Q000187:drug effects; D024821:Metabolic Syndrome / Q000188:drug therapy; D051379:Mice; D018345:Mice, Knockout; D009243:NAD / Q000378:metabolism*; D016660:NAD(P)H Dehydrogenase (Quinone); D009252:NADPH Dehydrogenase / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D009285:Naphthoquinones / Q000627:therapeutic use*; D009765:Obesity / Q000188:drug therapy* / Q000235:genetics*; D010084:Oxidation-Reduction; D010641:Phenotype; D015398:Signal Transduction / Q000502:physiology
chemical_list: D009285:Naphthoquinones; D009243:NAD; C014638:beta-lapachone; D016660:NAD(P)H Dehydrogenase (Quinone); C491732:Nqo1 protein, mouse; D009252:NADPH Dehydrogenase; D000263:Adenylate Kinase