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

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 BMAL...

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Veröffentlicht in:The Journal of biological chemistry 2014-09, Vol.289 (37), p.25925-25935
Hauptverfasser: Zhang, Deqiang, Tong, Xin, Arthurs, Blake, Guha, Anirvan, Rui, Liangyou, Kamath, Avani, Inoki, Ken, Yin, Lei
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container_end_page 25935
container_issue 37
container_start_page 25925
container_title The Journal of biological chemistry
container_volume 289
creator Zhang, Deqiang
Tong, Xin
Arthurs, Blake
Guha, Anirvan
Rui, Liangyou
Kamath, Avani
Inoki, Ken
Yin, Lei
description 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.
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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. 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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.</abstract><cop>United States</cop><pub>Elsevier Inc</pub><pmid>25063808</pmid><doi>10.1074/jbc.M114.567628</doi><tpages>11</tpages><oa>free_for_read</oa></addata></record>
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subjects Animals
ARNTL Transcription Factors - antagonists & inhibitors
ARNTL Transcription Factors - genetics
Eating - genetics
Gene Expression Regulation
Hepatocytes - metabolism
Insulin - metabolism
Insulin Resistance - genetics
Lipid Metabolism - genetics
Lipogenesis
Liver - metabolism
Mechanistic Target of Rapamycin Complex 2
Metabolism
Mice
Multiprotein Complexes - metabolism
Proto-Oncogene Proteins c-akt - metabolism
Signal Transduction
TOR Serine-Threonine Kinases - metabolism
title Liver Clock Protein BMAL1 Promotes de Novo Lipogenesis through Insulin-mTORC2-AKT Signaling
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