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- Title
Pharmacological Stimulation of NADH Oxidation Ameliorates Obesity and Related Phenotypes in Mice.
- Authors
Hwang, Jung Hwan; Kim, Dong Wook; Jo, Eun Jin; Kim, Yong Kyung; Jo, Young Suk; Park, Ji Hoon; Yoo, Sang Ku; Park, Myung Kyu; Kwak, Tae Hwan; Kho, Young Lira; Han, Jin; Choi, Hueng-Sik; Lee, Sang-Hee; Kim, Jin Man; Lee, InKyu; Kyung, Taeyoon; Jang, Cholsoon; Chung, Jongkyeong; Kweon, Gi Ryang; Shong, Minho
- Abstract
OBJECTIVE--Nicotinamide adenine dinucleotides (NAD[sup +] and NADH) play a crucial role in cellular energy metabolism, and a dysregulated NAD[sup +]-to-NADH ratio is implicated in metabolic syndrome. However, it is still unknown whether a modulating intracellular NAD[sup +]-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 13-lapachone (βL), a natural substrate of NADH:quinone oxidoreductase 1 (NQO1), to stimulate NADH oxidation. The βL-induced pharmacological effect on cellular energy metabolism was evaluated in cells derived from NQO1-deficient mice. In vivo therapeutic effects of βL on metabolic syndrome were examined in diet-induced obesity (DIO) and ob/ob mice. RESULTS--NQO1-dependent NADH oxidation by βL 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 βL 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 (PPARγ co-activator-1α, nuclear respiratory factor-1) and caloric restriction (Sirt1) consistent with the increased mitochondrial biogenesis and energy expenditure. CONCLUSIONS--Pharmacological activation of NADH oxidation by NQ01 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. Diabetes 58: 965-974, 2009
- Subjects
PHARMACOLOGY; NAD (Coenzyme); OXIDATION; OBESITY; PHENOTYPES; METABOLIC disorders; GENE expression; LABORATORY mice
- Publication
Diabetes, 2009, Vol 58, Issue 4, p965
- ISSN
0012-1797
- Publication type
Article
- DOI
10.2337/db08-1183