title: Tuberous sclerosis complex 1-mechanistic target of rapamycin complex 1 signaling determines brown-to-white adipocyte phenotypic switch.
abstract: Interconversion of white and brown adipocytes occurs between anabolic and catabolic states. The molecular mechanism regulating this phenotypic switch remains largely unknown. This study explores the role of tuberous sclerosis complex 1 (TSC1)-mechanistic target of rapamycin (mTOR) signaling in the conversion of brown to white adipose tissue (WAT). A colony of Fabp4-Tsc1(-/-) mice, in which the Tsc1 gene was specifically deleted by the fatty acid binding protein 4 (FABP4)-Cre, was established. Western blotting and immunostaining demonstrated the absence of TSC1 and activation of ribosomal protein S6 kinase 1, the downstream target of mTOR complex 1 (mTORC1) signaling, in the brown adipose tissues (BATs) of Fabp4-Tsc1(-/-) mice. Accumulation of lipid droplets in BAT was significantly increased. Levels of brown adipocyte markers were markedly downregulated, while white adipocyte markers were upregulated. Rapamycin reversed the conversion from BAT to WAT in Fabp4-Tsc1(-/-) mice. Deletion of the Tsc1 gene in cultured brown preadipocytes significantly increased the conversion to white adipocytes. FoxC2 mRNA, the transcriptional factor for brown adipocyte determination, was significantly decreased, while mRNAs for retinoblastoma protein, p107 and RIP140, the transcriptional factors for white adipocyte determination, increased in the BAT of Fabp4-Tsc1(-/-) mice. Our study demonstrates that TSC1-mTORC1 signaling contributes to the brown-to-white adipocyte phenotypic switch.
authors.affiliation: Department of Physiology and Pathophysiology, Peking University Health Science Center, Beijing, China Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Beijing, China Department of Pathology, Central Hospital of Zibo, Zibo, China.
authors.forename: Xinxin
authors.initials: X
authors.lastname: Xiang
authors.affiliation: Department of Physiology and Pathophysiology, Peking University Health Science Center, Beijing, China Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Beijing, China.
authors.forename: He
authors.initials: H
authors.lastname: Lan
authors.affiliation: Department of Physiology and Pathophysiology, Peking University Health Science Center, Beijing, China Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Beijing, China.
authors.forename: Hong
authors.initials: H
authors.lastname: Tang
authors.affiliation: Department of Physiology and Pathophysiology, Peking University Health Science Center, Beijing, China Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Beijing, China.
authors.forename: Fang
authors.initials: F
authors.lastname: Yuan
authors.affiliation: Department of Physiology and Pathophysiology, Peking University Health Science Center, Beijing, China Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Beijing, China.
authors.forename: Yanhui
authors.initials: Y
authors.lastname: Xu
authors.affiliation: Department of Physiology and Pathophysiology, Peking University Health Science Center, Beijing, China Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Beijing, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Zhao
authors.affiliation: Department of Physiology and Pathophysiology, Peking University Health Science Center, Beijing, China Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Beijing, China weizhenzhang@bjmu.edu.cn yinli@bjmu.edu.cn.
authors.forename: Yin
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Physiology and Pathophysiology, Peking University Health Science Center, Beijing, China Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Beijing, China Department of Surgery, University of Michigan, Ann Arbor, MI weizhenzhang@bjmu.edu.cn yinli@bjmu.edu.cn.
authors.forename: Weizhen
authors.initials: W
authors.lastname: Zhang
mesh_terms: D052437:Adipocytes, Brown / Q000502:physiology*; D052438:Adipocytes, White / Q000502:physiology*; D000818:Animals; D002478:Cells, Cultured; D005786:Gene Expression Regulation / Q000502:physiology; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D046912:Multiprotein Complexes / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D020123:Sirolimus / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D059467:Transcriptome; D000077004:Tuberous Sclerosis Complex 1 Protein; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D046912:Multiprotein Complexes; C000624651:Tsc1 protein, mouse; D000077004:Tuberous Sclerosis Complex 1 Protein; D025521:Tumor Suppressor Proteins; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus