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 |
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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. Thus, our study uncovered a novel metabolic function of hepatic BMAL1 that promotes de novo lipogenesis via the insulin-mTORC2-AKT signaling during refeeding.</description><identifier>ISSN: 0021-9258</identifier><identifier>EISSN: 1083-351X</identifier><identifier>DOI: 10.1074/jbc.M114.567628</identifier><identifier>PMID: 25063808</identifier><language>eng</language><publisher>United States: Elsevier Inc</publisher><subject>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</subject><ispartof>The Journal of biological chemistry, 2014-09, Vol.289 (37), p.25925-25935</ispartof><rights>2014 © 2014 ASBMB. Currently published by Elsevier Inc; originally published by American Society for Biochemistry and Molecular Biology.</rights><rights>2014 by The American Society for Biochemistry and Molecular Biology, Inc.</rights><rights>2014 by The American Society for Biochemistry and Molecular Biology, Inc. 2014</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c509t-612fd03c342521c0640e3b1c08221b2e012789971c5fb918d2007547123d8d633</citedby><cites>FETCH-LOGICAL-c509t-612fd03c342521c0640e3b1c08221b2e012789971c5fb918d2007547123d8d633</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4162191/pdf/$$EPDF$$P50$$Gpubmedcentral$$H</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4162191/$$EHTML$$P50$$Gpubmedcentral$$H</linktohtml><link.rule.ids>230,314,723,776,780,881,27901,27902,53766,53768</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/25063808$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Zhang, Deqiang</creatorcontrib><creatorcontrib>Tong, Xin</creatorcontrib><creatorcontrib>Arthurs, Blake</creatorcontrib><creatorcontrib>Guha, Anirvan</creatorcontrib><creatorcontrib>Rui, Liangyou</creatorcontrib><creatorcontrib>Kamath, Avani</creatorcontrib><creatorcontrib>Inoki, Ken</creatorcontrib><creatorcontrib>Yin, Lei</creatorcontrib><title>Liver Clock Protein BMAL1 Promotes de Novo Lipogenesis through Insulin-mTORC2-AKT Signaling</title><title>The Journal of biological chemistry</title><addtitle>J Biol Chem</addtitle><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.</description><subject>Animals</subject><subject>ARNTL Transcription Factors - antagonists & inhibitors</subject><subject>ARNTL Transcription Factors - genetics</subject><subject>Eating - genetics</subject><subject>Gene Expression Regulation</subject><subject>Hepatocytes - metabolism</subject><subject>Insulin - metabolism</subject><subject>Insulin Resistance - genetics</subject><subject>Lipid Metabolism - genetics</subject><subject>Lipogenesis</subject><subject>Liver - metabolism</subject><subject>Mechanistic Target of Rapamycin Complex 2</subject><subject>Metabolism</subject><subject>Mice</subject><subject>Multiprotein Complexes - metabolism</subject><subject>Proto-Oncogene Proteins c-akt - metabolism</subject><subject>Signal Transduction</subject><subject>TOR Serine-Threonine Kinases - metabolism</subject><issn>0021-9258</issn><issn>1083-351X</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2014</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp1kcGP1CAUh4nRuLOrZ2-Go5fO8qC05WIyTtTd2HWNjomJB9LSNx3WFkZoJ_G_l8msGz3IBR587wfhI-QFsCWwMr-8a83yBiBfyqIsePWILIBVIhMSvj0mC8Y4ZIrL6oycx3jH0sgVPCVnXLJCVKxakO-1PWCg68GbH_RT8BNaR9_crGo4VmOqI-2QfvQHT2u79z06jDbSaRf83O_otYvzYF02bm4_r3m2-rChX2zvmrTXPyNPts0Q8fn9fEG-vnu7WV9l9e376_WqzoxkasoK4NuOCSNyLjkYVuQMRZsWFefQcmTAy0qpEozctgqqjjNWyrwELrqqK4S4IK9Pufu5HbEz6KbQDHof7NiEX9o3Vv974uxO9_6gcyg4KEgBr-4Dgv85Y5z0aKPBYWgc-jlqkAWoUpUiT-jlCTXBxxhw-3ANMH1UopMSfVSiT0pSx8u_X_fA_3GQAHUCMP3RwWLQ0Vh0Bjsb0Ey68_a_4b8BxK-ZJg</recordid><startdate>20140912</startdate><enddate>20140912</enddate><creator>Zhang, Deqiang</creator><creator>Tong, Xin</creator><creator>Arthurs, Blake</creator><creator>Guha, Anirvan</creator><creator>Rui, Liangyou</creator><creator>Kamath, Avani</creator><creator>Inoki, Ken</creator><creator>Yin, Lei</creator><general>Elsevier Inc</general><general>American Society for Biochemistry and Molecular Biology</general><scope>6I.</scope><scope>AAFTH</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope><scope>5PM</scope></search><sort><creationdate>20140912</creationdate><title>Liver Clock Protein BMAL1 Promotes de Novo Lipogenesis through Insulin-mTORC2-AKT Signaling</title><author>Zhang, Deqiang ; Tong, Xin ; Arthurs, Blake ; Guha, Anirvan ; Rui, Liangyou ; Kamath, Avani ; Inoki, Ken ; Yin, Lei</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c509t-612fd03c342521c0640e3b1c08221b2e012789971c5fb918d2007547123d8d633</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2014</creationdate><topic>Animals</topic><topic>ARNTL Transcription Factors - antagonists & inhibitors</topic><topic>ARNTL Transcription Factors - genetics</topic><topic>Eating - genetics</topic><topic>Gene Expression Regulation</topic><topic>Hepatocytes - metabolism</topic><topic>Insulin - metabolism</topic><topic>Insulin Resistance - genetics</topic><topic>Lipid Metabolism - genetics</topic><topic>Lipogenesis</topic><topic>Liver - metabolism</topic><topic>Mechanistic Target of Rapamycin Complex 2</topic><topic>Metabolism</topic><topic>Mice</topic><topic>Multiprotein Complexes - metabolism</topic><topic>Proto-Oncogene Proteins c-akt - metabolism</topic><topic>Signal Transduction</topic><topic>TOR Serine-Threonine Kinases - metabolism</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Zhang, Deqiang</creatorcontrib><creatorcontrib>Tong, Xin</creatorcontrib><creatorcontrib>Arthurs, Blake</creatorcontrib><creatorcontrib>Guha, Anirvan</creatorcontrib><creatorcontrib>Rui, Liangyou</creatorcontrib><creatorcontrib>Kamath, Avani</creatorcontrib><creatorcontrib>Inoki, Ken</creatorcontrib><creatorcontrib>Yin, Lei</creatorcontrib><collection>ScienceDirect Open Access Titles</collection><collection>Elsevier:ScienceDirect:Open Access</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>The Journal of biological chemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Zhang, Deqiang</au><au>Tong, Xin</au><au>Arthurs, Blake</au><au>Guha, Anirvan</au><au>Rui, Liangyou</au><au>Kamath, Avani</au><au>Inoki, Ken</au><au>Yin, Lei</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Liver Clock Protein BMAL1 Promotes de Novo Lipogenesis through Insulin-mTORC2-AKT Signaling</atitle><jtitle>The Journal of biological chemistry</jtitle><addtitle>J Biol Chem</addtitle><date>2014-09-12</date><risdate>2014</risdate><volume>289</volume><issue>37</issue><spage>25925</spage><epage>25935</epage><pages>25925-25935</pages><issn>0021-9258</issn><eissn>1083-351X</eissn><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.</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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