title: Liver clock protein BMAL1 promotes de novo lipogenesis through insulin-mTORC2-AKT signaling.
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.
authors: From the Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, Michigan 48109.
authors: Deqiang
authors: D
authors: Zhang
authors: From the Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, Michigan 48109.
authors: Xin
authors: X
authors: Tong
authors: From the Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, Michigan 48109.
authors: Blake
authors: B
authors: Arthurs
authors: From the Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, Michigan 48109.
authors: Anirvan
authors: A
authors: Guha
authors: From the Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, Michigan 48109.
authors: Liangyou
authors: L
authors: Rui
authors: From the Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, Michigan 48109.
authors: Avani
authors: A
authors: Kamath
authors: From the Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, Michigan 48109.
authors: Ken
authors: K
authors: Inoki
authors: From the Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, Michigan 48109 Leiyin@umich.edu.
authors: Lei
authors: L
authors: Yin
mesh_terms: D056930:ARNTL Transcription Factors / Q000037:antagonists & inhibitors / Q000235:genetics*; D000818:Animals; D004435:Eating / Q000235:genetics; D005786:Gene Expression Regulation; D022781:Hepatocytes / Q000378:metabolism; D007328:Insulin / Q000378:metabolism*; D007333:Insulin Resistance / Q000235:genetics; D050356:Lipid Metabolism / Q000235:genetics; D050155:Lipogenesis; D008099:Liver / Q000378:metabolism; D000076225:Mechanistic Target of Rapamycin Complex 2; D051379:Mice; D046912:Multiprotein Complexes / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*
chemical_list: D056930:ARNTL Transcription Factors; C538961:Bmal1 protein, mouse; D007328:Insulin; D046912:Multiprotein Complexes; D000076225:Mechanistic Target of Rapamycin Complex 2; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases
keywords: Akt; Circadian Clock; Insulin Signaling; Lipid Metabolism; Lipogenesis; Liver; Rictor-mTORC2