Adipocyte NADH dehydrogenase reverses circadian and diet-induced metabolic syndrome

Abstract Circadian clocks are internal timing systems that enable organisms to anticipate and adapt to daily environmental changes. These rhythms arise from a transcription–translation feedback loop in which CLOCK and BMAL1 regulate the expression of thousands of genes, including their repressors PER and CRY. Disruption of circadian rhythms contributes to obesity, metabolic disease and cancer, yet how the clock maintains metabolic homeostasis remains limited. Here we report that the clock regulates oxidative metabolism in adipocytes through diurnal complex I respiration. Disrupting the clock in male mice via adipocyte-specific genetic deletion or high-fat-diet feeding reduces complex I respiration in adipocytes, leading to suppression of the peroxisome proliferator-activated receptor and insulin signalling pathways. In contrast, restoring complex I function by expressing yeast NDI1 in adipocytes protects against diet-induced and circadian-induced metabolic dysfunction independently of weight gain. These findings reveal that adipocyte circadian disruption impairs metabolic health through mitochondrial complex I dysfunction, establishing clock control of complex I as a key regulator of metabolic homeostasis.