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

• Published in: Molecular cell 2020-02, Vol.77 (3), p.600-617.e4
• Main Authors: Nguyen, Hai P., Yi, Danielle, Lin, Frances, Viscarra, Jose A., Tabuchi, Chihiro, Ngo, Katina, Shin, Gawon, Lee, Angus Yiu-fai, Wang, Yuhui, Sul, Hei Sook
• Format: Article
• Language: English
• Subjects: Adipose Tissue, Brown - metabolism; Adipose Tissue, White - metabolism; Animals; Apoptosis Regulatory Proteins - metabolism; Apoptosis Regulatory Proteins - physiology; Diet; Energy Metabolism; Glucose - metabolism; Glycolysis - physiology; HEK293 Cells; Humans; Insulin Resistance; Lipid Droplets - metabolism; Male; Mice, Inbred C57BL; Mice, Knockout; Mitochondrial Membranes - metabolism; Mitochondrial Proteins - metabolism; Mitochondrial Proteins - physiology; Multienzyme Complexes - metabolism; NAD - metabolism; NAD - physiology; NADH, NADPH Oxidoreductases - metabolism; Obesity - metabolism; Oxidation-Reduction; Oxygen Consumption; Thermogenesis - physiology; Uncoupling Protein 1 - metabolism
• ISSN: 1097-2765; 1097-4164
• DOI: 10.1016/j.molcel.2019.12.002

Brown adipose tissue (BAT) is highly metabolically active tissue that dissipates 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 an 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 the electron transport chain (ETC) for fueling thermogenesis. Aifm2 in BAT and subcutaneous white adipose tissue (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. [Display omitted] •Aifm2 is expressed specifically in brown adipose tissue (BAT)•Aifm2 regenerates NAD to support robust glycolysis for thermogenesis•Glucose oxidation is critical for thermogenesis in a fed state•Aifm2 translocated from LD to mitochondria supports ETC for thermogenesis Aifm2, a brown-adipose-tissue-specific, lipid-droplet-associated NADH oxidase, associates with the mitochondrial inner membrane to regenerate cytosolic NAD for robust glycolysis and to support ETC for thermogenesis.