Time Restricted Feeding Mitigates Obesity Through Adipocyte Thermogenesis

In obesity, misalignment of feeding time with the light/dark environment results in disruption of peripheral circadian clocks. Conversely, restricting feeding to the active period mitigates metabolic syndrome through mechanisms that remain unknown. Here we show that adipocyte thermogenesis is essential for the healthful metabolic response to time restricted feeding. Genetic enhancement of adipocyte thermogenesis through ablation of Zfp423 attenuates obesity caused by circadian mistimed high fat diet feeding through a mechanism involving creatine metabolism. Circadian control of adipocyte creatine metabolism underlies timing of diet-induced thermogenesis, and enhancement of adipocyte circadian rhythms through overexpression of the clock activator Bmal1 ameliorates metabolic complications during diet induced obesity. These findings establish creatine mediated diet-induced thermogenesis as a bioenergetic mechanism driving metabolic benefits during time-restricted feeding. 36 ATAC-seq samples at 6 time points (3 replicates), 35 RNA-seq samples at 6 time points (3 replicates, 1 replicate missing BAT ZT17 RNA 3), 2 BMAL1 ChIP samples and 1 input ChIP sample.