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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 β-lapachone (ßL), 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-deflcient nuce. In vivo therapeutic effects of βL on metabolic syndrome were examined in dietinduced 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 coactivator-lα, nuclear respiratory factor-1) and caloric restriction (Sirtl) 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. Diabetes 58: 965-974, 2009
Metabolic syndrome comprises a constellation of specific cardiovascular disease risk factors whose underlying pathophysiology is related to insulin resistance (1). All the components of metabolic syndrome such as dyslipidemia, high blood pressure, glucose intolerance, and liver and muscle fat infiltration are related to central obesity. It has been reported that the imbalance between energy intake and expenditure is clearly related to obesity and metabolic disorders (2). Less calorie intake and more energy expenditure through exercise are the most effective modalities for the prevention of metabolic syndrome (3). Calorie restriction (4) and increased physical activity, in fact, have been known to prevent and reverse the phenotypes of metabolic syndrome by activating metabolic regulator proteins such as Sirtl, AMP-activated protein kinase (AMPK), and PPARγ coactivator-1α...