Pharmacological Stimulation of NADH Oxidation Ameliorates Obesity and Related Phenotypes in Mice

Abstract

OBJECTIVENicotinamide 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 METHODSWe 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.RESULTSNQO1-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-1α, nuclear respiratory factor-1) and caloric restriction (Sirt1) consistent with the increased mitochondrial biogenesis and energy expenditure.CONCLUSIONSPharmacological 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.

Overexpression of CYB5R3 and NQO1, two NAD+‐producing enzymes, mimics aspects of caloric restriction

“…NQO1 catalyzes a two‐electron quinone reduction using NADH or NADPH as cofactor. In addition to its well‐known antioxidant properties [reviewed in (Ross & Siegel, 2017)], NQO1 exerts significant metabolic functions by conferring protection against obesity, hypertension, arterial restenosis, renal injury, and neurodegenerative disorders (Chhetri, King & Gueven, 2017; Hwang et al., 2009; Kim et al., 2011; Son et al., 2015). The C609T (Pro187Ser) null polymorphism of the NQO1 gene is associated with increased risk of complications related to metabolic syndrome, Alzheimer's disease, and an overall increased risk of cancer in humans (Chhetri et al., 2017; Lajin & Alachkar, 2013; Martinez‐Hernandez et al., 2015; Ramprasath et al., 2012).…”

β-Lapachone Prevents Diet-Induced Obesity by Increasing Energy Expenditure and Stimulating the Browning of White Adipose Tissue via Downregulation of miR-382 Expression

“…Previous studies suggested that BLC facilitates the NADH: quinone oxidoreductase 1-dependent oxidation of NADH to NAD + . Moreover, stimulated NADH oxidation by BLC ameliorates obesity by increasing mitochondrial biogenesis (16). We therefore hypothesized that the antiobesity effect of BLC may be associated with the upregulation of energy expenditure and the stimulation of fat browning.…”

“…Many studies have reported that NAD + and NADH regulate energy metabolism and that the increased intracellular NAD + -to-NADH ratio activates sirtuin 1 (Sirt1) (16)(17)(18). Previous studies suggested that BLC facilitates the NADH: quinone oxidoreductase 1-dependent oxidation of NADH to NAD + .…”

Inhibition of NAD(P)H:Quinone Oxidoreductase 1 by Dicumarol Reduces Tight Junction in Human Colonic Epithelial Cells

“…이 과정을 통해서 에너지 대사 중개 물질로 잘 알려진 NAD와 NADH의 세포 속 비율이 조절 된다 [4,6,15]. NQO1은 세포 속에서 형성된 활성산소(reactive oxygen species)를 제거해주는 항산화제 역할을 하는 것으로 도 알려져 있다 [22,23].…”