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 dysregulated NAD⁺/NADH ratio is implicated in metabolic syndrome. However, it is still unknown that modulating intracellular NAD⁺/NADH ratio is beneficial in treating metabolic syndrome. Thus, 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 (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 with activation of AMP-activated protein kinase (AMPK) and carnitine palmitoyltransferase (CPT) and suppression of acetyl-CoA carboxylase (ACC) 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 (PGC-1α, NRF-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.