Aifm2, a NADH Oxidase, Supports Robust Glycolysis and Is Required for Cold- and Diet-Induced Thermogenesis

Abstract

Brown adipose tissue (BAT) is highly metabolically active tissue to dissipate energy via UCP1 as heat, and BAT mass is correlated negatively with obesity. The presence of BAT/BAT-like tissue in humans renders BAT as attractive target against obesity and insulin resistance. Here, we identify Aifm2, a NADH oxidoreductase domain containing flavoprotein, as a lipid droplet (LD) associated protein highly enriched in BAT. Aifm2 is induced by cold, as well as by diet. Upon cold or β-adrenergic stimulation, Aifm2 associates with the outer side of the mitochondrial inner membrane. As a unique BAT-specific first mammalian NDE (external NADH dehydrogenase)-like enzyme, Aifm2 oxidizes NADH to maintain high cytosolic NAD levels in supporting robust glycolysis and to transfer electrons to ETC for fueling thermogenesis. Aifm2 in BAT and subcutaneous WAT promotes oxygen consumption, uncoupled respiration and heat production during cold- and diet-induced thermogenesis. Aifm2, thus, can ameliorate diet-induced obesity and insulin resistance. Aifm2, a brown adipose tissue specific lipid-droplet associated NADH oxidase, associates with mitochondrial inner membrane to regenerate cytosolic NAD for robust glycolysis and to support ETC for thermogenesis.