Fatty liver disease is associated with obesity and type 2 diabetes, and hepatic lipid accumulation may contribute to insulin resistance. Histone deacetylase 3 (Hdac3) controls the circadian rhythm of hepatic lipogenesis. Here we show that, despite severe hepatosteatosis, mice with liver-specific depletion of Hdac3 have higher insulin sensitivity without any changes in insulin signaling or body weight compared to wild-type mice. Hdac3 depletion reroutes metabolic precursors towards lipid synthesis and storage within lipid droplets and away from hepatic glucose production. Perilipin 2, which coats lipid droplets, is markedly induced upon Hdac3 depletion and contributes to the development of both steatosis and improved tolerance to glucose. These findings suggest that the sequestration of hepatic lipids in perilipin 2–coated droplets ameliorates insulin resistance and establish Hdac3 as a pivotal epigenomic modifier that integrates signals from the circadian clock in the regulation of hepatic intermediary metabolism.
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We thank J. Millar and the Metabolic Tracer Resource at the Penn Institute for Diabetes, Obesity and Metabolism for the lipogenesis flux assay. We thank the Mouse Metabolic Phenotyping Core and the Viral Vector Core at Penn Diabetes Research Center (P30 DK19525) and the Penn Digestives Disease Center Morphology Core (P30 DK050306) at the University of Pennsylvania. We thank the Vanderbilt (DK59637) and Yale (U24 DK059635) Mouse Metabolic Phenotyping Centers and the Children's Hospital of Philadelphia Pathology Core. We thank B. Agarwal and S. Mullican for helpful discussion. This work was supported by US National Institutes of Health grants R37 DK43806 (M.A.L.), P01 DK49210 (M.A.L., M.J. Birnbaum and R.S.A.) and R01 DK40936 (G.I.S.), R01 DK075017 (C.S.), the Department of Veteran Affairs Merit Review Program (T.G.U.), grant F32 DK079572 (R.A.M.), the JPB Foundation and the Cox Institute for Medical Research.
The authors declare no competing financial interests.
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