title: Grb10 promotes lipolysis and thermogenesis by phosphorylation-dependent feedback inhibition of mTORC1.
abstract: Identification of key regulators of lipid metabolism and thermogenic functions has important therapeutic implications for the current obesity and diabetes epidemic. Here, we show that Grb10, a direct substrate of mechanistic/mammalian target of rapamycin (mTOR), is expressed highly in brown adipose tissue, and its expression in white adipose tissue is markedly induced by cold exposure. In adipocytes, mTOR-mediated phosphorylation at Ser501/503 switches the binding preference of Grb10 from the insulin receptor to raptor, leading to the dissociation of raptor from mTOR and downregulation of mTOR complex 1 (mTORC1) signaling. Fat-specific disruption of Grb10 increased mTORC1 signaling in adipose tissues, suppressed lipolysis, and reduced thermogenic function. The effects of Grb10 deficiency on lipolysis and thermogenesis were diminished by rapamycin administration in vivo. Our study has uncovered a unique feedback mechanism regulating mTORC1 signaling in adipose tissues and identified Grb10 as a key regulator of adiposity, thermogenesis, and energy expenditure.
authors.affiliation: Department of Pharmacology, University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Drive, San Antonio, TX 78229, USA; Metabolic Syndrome Research Center and Diabetes Center, Key Laboratory of Diabetes Immunology, Ministry of Education, Second Xiangya Hospital, Central South University, 139 Middle Renmin Road, Changsha, Hunan 410011, China.
authors.forename: Meilian
authors.initials: M
authors.lastname: Liu
authors.affiliation: Department of Pharmacology, University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Drive, San Antonio, TX 78229, USA; Metabolic Syndrome Research Center and Diabetes Center, Key Laboratory of Diabetes Immunology, Ministry of Education, Second Xiangya Hospital, Central South University, 139 Middle Renmin Road, Changsha, Hunan 410011, China.
authors.forename: Juli
authors.initials: J
authors.lastname: Bai
authors.affiliation: Department of Pharmacology, University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Drive, San Antonio, TX 78229, USA; Metabolic Syndrome Research Center and Diabetes Center, Key Laboratory of Diabetes Immunology, Ministry of Education, Second Xiangya Hospital, Central South University, 139 Middle Renmin Road, Changsha, Hunan 410011, China.
authors.forename: Sijia
authors.initials: S
authors.lastname: He
authors.affiliation: Department of Cellular and Structural Biology, University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Drive, San Antonio, TX 78229, USA.
authors.forename: Ricardo
authors.initials: R
authors.lastname: Villarreal
authors.affiliation: Department of Pharmacology, University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Drive, San Antonio, TX 78229, USA.
authors.forename: Derong
authors.initials: D
authors.lastname: Hu
authors.affiliation: Department of Pharmacology, University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Drive, San Antonio, TX 78229, USA; The Department of Microbiology, School of Basic Medicine, Xinjiang Medical University, 393 Xinyi Road, Urumqi, Xinjiang 830011, China.
authors.forename: Chuntao
authors.initials: C
authors.lastname: Zhang
authors.affiliation: Department of Cellular and Structural Biology, University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Drive, San Antonio, TX 78229, USA.
authors.forename: Xin
authors.initials: X
authors.lastname: Yang
authors.affiliation: Department of Cellular and Structural Biology, University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Drive, San Antonio, TX 78229, USA.
authors.forename: Huiyun
authors.initials: H
authors.lastname: Liang
authors.affiliation: Department of Pharmacology, University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Drive, San Antonio, TX 78229, USA.
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Slaga
authors.affiliation: Department of Cell Biology, Harvard Medical School, 240 Longwood Avenue, Boston, MA 02115, USA.
authors.forename: Yonghao
authors.initials: Y
authors.lastname: Yu
authors.affiliation: Metabolic Syndrome Research Center and Diabetes Center, Key Laboratory of Diabetes Immunology, Ministry of Education, Second Xiangya Hospital, Central South University, 139 Middle Renmin Road, Changsha, Hunan 410011, China.
authors.forename: Zhiguang
authors.initials: Z
authors.lastname: Zhou
authors.affiliation: Department of Cell Biology, Harvard Medical School, 240 Longwood Avenue, Boston, MA 02115, USA.
authors.forename: John
authors.initials: J
authors.lastname: Blenis
authors.affiliation: Touchstone Diabetes Center, Department of Internal Medicine, and Department of Cell Biology, UT Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390-8549, USA.
authors.forename: Philipp E
authors.initials: PE
authors.lastname: Scherer
authors.affiliation: Department of Cellular and Structural Biology, University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Drive, San Antonio, TX 78229, USA.
authors.forename: Lily Q
authors.initials: LQ
authors.lastname: Dong
authors.affiliation: Department of Pharmacology, University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Drive, San Antonio, TX 78229, USA; Metabolic Syndrome Research Center and Diabetes Center, Key Laboratory of Diabetes Immunology, Ministry of Education, Second Xiangya Hospital, Central South University, 139 Middle Renmin Road, Changsha, Hunan 410011, China. Electronic address: liuf@uthscsa.edu.
authors.forename: Feng
authors.initials: F
authors.lastname: Liu
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D002001:Adipose Tissue, Brown / Q000378:metabolism; D052436:Adipose Tissue, White / Q000378:metabolism; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D002478:Cells, Cultured; D003080:Cold Temperature; D058639:Cold-Shock Response; D003920:Diabetes Mellitus; D004734:Energy Metabolism / Q000502:physiology*; D025461:Feedback, Physiological; D051383:GRB10 Adaptor Protein / Q000096:biosynthesis / Q000378:metabolism*; D007333:Insulin Resistance; D008066:Lipolysis / Q000502:physiology*; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D018345:Mice, Knockout; D046912:Multiprotein Complexes / Q000037:antagonists & inhibitors / Q000378:metabolism*; D009765:Obesity; D019869:Phosphatidylinositol 3-Kinases; D010766:Phosphorylation; D011485:Protein Binding; D051057:Proto-Oncogene Proteins c-akt; D011972:Receptor, Insulin / Q000378:metabolism; D000076223:Regulatory-Associated Protein of mTOR; D015398:Signal Transduction / Q000502:physiology; D020123:Sirolimus / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D022722:Thermogenesis / Q000502:physiology*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000903:Antibiotics, Antineoplastic; D051383:GRB10 Adaptor Protein; D000076222:Mechanistic Target of Rapamycin Complex 1; D046912:Multiprotein Complexes; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D011972:Receptor, Insulin; D000076223:Regulatory-Associated Protein of mTOR; D020123:Sirolimus; D058570:TOR Serine-Threonine Kinases; C495959:Grb10 protein, mouse; C540162:Rptor protein, mouse
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