Liver clock protein BMAL1 promotes de novo lipogenesis through insulin-mTORC2-AKT signaling [Signal Transduction]

July 25th, 2014 by Zhang, D., Tong, X., Arthurs, B., Guha, A., Rui, L., Kamath, A., Inoki, K., Yin, L.

The clock protein BMAL1 participates in circadian regulation of lipid metabolism, but its contribution to insulin-AKT-regulated hepatic lipid synthesis is unclear. Here we used both Bmal1-/- and acute liver-specific Bmal1-depleted mice to study the role of BMAL1 in refeeding-induced de novo lipogenesis in the liver. Both global deficiency and acute hepatic depletion of Bmal1 reduced lipogenic gene expression in the liver upon refeeding. Conversely, overexpression of Bmal1 in mouse liver by adenovirus was sufficient to elevate the levels of mRNA of lipogenic enzymes. Bmal1-/- primary mouse hepatocytes displayed decreased levels of de novo lipogenesis and lipogenic enzymes, supporting the notion that that BMAL1 regulates lipid synthesis in hepatocytes in a cell-autonomous manner. Both refed mouse liver and insulin-treated primary mouse hepatocytes showed impaired AKT activation in the case of either Bmal1 deficiency or Bmal1 depletion by adenoviral shRNA. Restoring AKT activity by a constitutively active mutant of AKT nearly normalized de novo lipogenesis in Bmal1-/- hepatocytes. Finally, Bmal1 deficiency or knockdown decreased the protein abundance of RICTOR, the key component of the mTORC2 complex, without affecting the gene expression of key factors of insulin signaling. Thus, our study uncovered a novel metabolic function of hepatic BMAL1, which promotes de novo lipogenesis via the insulin-mTORC2-AKT signaling during refeeding.