Liver Clock Protein BMAL1 Promotes de Novo Lipogenesis through Insulin-mTORC2-AKT Signaling

Deqiang Zhang,Xin Tong,Blake Arthurs,Anirvan Guha,Liangyou Rui,Avani Kamath,Ken Inoki,Lei Yin

doi:10.1074/jbc.m114.567628

Deqiang Zhang, Xin Tong + Show 6 more

Open Access

https://doi.org/10.1074/jbc.m114.567628

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Abstract

The clock protein BMAL1 (brain and muscle Arnt-like protein 1) 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, Bmal1 overexpression 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 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 that promotes de novo lipogenesis via the insulin-mTORC2-AKT signaling during refeeding.

Highlights

The role of BMAL1 in lipogenesis in the liver is unknown
In this report we demonstrate for the first time that BMAL1 is both necessary and sufficient to promote the expression of lipid synthesis enzymes in the mouse liver and de novo lipogenesis in mouse hepatocytes
Because insulin signaling has been reported to modulate the molecular clock in cells [36], we asked whether insulin could induce the expression of Dbp and Per2 in a cellautonomous fashion in isolated Primary mouse hepatocytes (PMHs)

Summary

Introduction

The role of BMAL1 in lipogenesis in the liver is unknown. Results: BMAL1 is necessary and required for driving lipogenic gene expression and AKT activation in vivo and in vitro in response to refeeding and insulin. Our study uncovered a novel metabolic function of hepatic BMAL1 that promotes de novo lipogenesis via the insulin-mTORC2-AKT signaling during refeeding. In this report we demonstrate for the first time that BMAL1 is both necessary and sufficient to promote the expression of lipid synthesis enzymes in the mouse liver and de novo lipogenesis in mouse hepatocytes.

Results

Conclusion