PMID- 24746805 OWN - NLM STAT- MEDLINE DCOM- 20150615 LR - 20211203 IS - 1932-7420 (Electronic) IS - 1550-4131 (Print) IS - 1550-4131 (Linking) VI - 19 IP - 6 DP - 2014 Jun 3 TI - Grb10 promotes lipolysis and thermogenesis by phosphorylation-dependent feedback inhibition of mTORC1. PG - 967-80 LID - S1550-4131(14)00123-5 [pii] LID - 10.1016/j.cmet.2014.03.018 [doi] AB - 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. CI - Copyright (c) 2014 Elsevier Inc. All rights reserved. FAU - Liu, Meilian AU - Liu M AD - 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. FAU - Bai, Juli AU - Bai J AD - 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. FAU - He, Sijia AU - He S AD - 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. FAU - Villarreal, Ricardo AU - Villarreal R AD - Department of Cellular and Structural Biology, University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Drive, San Antonio, TX 78229, USA. FAU - Hu, Derong AU - Hu D AD - Department of Pharmacology, University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Drive, San Antonio, TX 78229, USA. FAU - Zhang, Chuntao AU - Zhang C AD - 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. FAU - Yang, Xin AU - Yang X AD - Department of Cellular and Structural Biology, University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Drive, San Antonio, TX 78229, USA. FAU - Liang, Huiyun AU - Liang H AD - Department of Cellular and Structural Biology, University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Drive, San Antonio, TX 78229, USA. FAU - Slaga, Thomas J AU - Slaga TJ AD - Department of Pharmacology, University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Drive, San Antonio, TX 78229, USA. FAU - Yu, Yonghao AU - Yu Y AD - Department of Cell Biology, Harvard Medical School, 240 Longwood Avenue, Boston, MA 02115, USA. FAU - Zhou, Zhiguang AU - Zhou Z AD - 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. FAU - Blenis, John AU - Blenis J AD - Department of Cell Biology, Harvard Medical School, 240 Longwood Avenue, Boston, MA 02115, USA. FAU - Scherer, Philipp E AU - Scherer PE AD - 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. FAU - Dong, Lily Q AU - Dong LQ AD - Department of Cellular and Structural Biology, University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Drive, San Antonio, TX 78229, USA. FAU - Liu, Feng AU - Liu F AD - 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. LA - eng GR - P01 DK088761/DK/NIDDK NIH HHS/United States GR - DK099110/DK/NIDDK NIH HHS/United States GR - P01-DK088761/DK/NIDDK NIH HHS/United States GR - GM51405/GM/NIGMS NIH HHS/United States GR - R01 DK69930/DK/NIDDK NIH HHS/United States GR - DK55758/DK/NIDDK NIH HHS/United States GR - R01 DK099110/DK/NIDDK NIH HHS/United States GR - R01 DK055758/DK/NIDDK NIH HHS/United States GR - R01 DK100697/DK/NIDDK NIH HHS/United States GR - R01 DK069930/DK/NIDDK NIH HHS/United States GR - R01 GM051405/GM/NIGMS NIH HHS/United States GR - R56 DK069930/DK/NIDDK NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20140417 PL - United States TA - Cell Metab JT - Cell metabolism JID - 101233170 RN - 0 (Adaptor Proteins, Signal Transducing) RN - 0 (Antibiotics, Antineoplastic) RN - 0 (Grb10 protein, mouse) RN - 0 (Multiprotein Complexes) RN - 0 (Regulatory-Associated Protein of mTOR) RN - 0 (Rptor protein, mouse) RN - 151441-47-3 (GRB10 Adaptor Protein) RN - EC 2.7.10.1 (Receptor, Insulin) RN - EC 2.7.11.1 (Mechanistic Target of Rapamycin Complex 1) RN - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt) RN - EC 2.7.11.1 (TOR Serine-Threonine Kinases) RN - W36ZG6FT64 (Sirolimus) SB - IM CIN - Cell Cycle. 2014;13(17):2643-4. PMID: 25486344 MH - Adaptor Proteins, Signal Transducing/metabolism MH - Adipose Tissue, Brown/metabolism MH - Adipose Tissue, White/metabolism MH - Animals MH - Antibiotics, Antineoplastic/pharmacology MH - Cells, Cultured MH - Cold Temperature MH - Cold-Shock Response MH - Diabetes Mellitus MH - Energy Metabolism/*physiology MH - Feedback, Physiological MH - GRB10 Adaptor Protein/biosynthesis/*metabolism MH - Insulin Resistance MH - Lipolysis/*physiology MH - Mechanistic Target of Rapamycin Complex 1 MH - Mice MH - Mice, Knockout MH - Multiprotein Complexes/antagonists & inhibitors/*metabolism MH - Obesity MH - Phosphatidylinositol 3-Kinases MH - Phosphorylation MH - Protein Binding MH - Proto-Oncogene Proteins c-akt MH - Receptor, Insulin/metabolism MH - Regulatory-Associated Protein of mTOR MH - Signal Transduction/physiology MH - Sirolimus/pharmacology MH - TOR Serine-Threonine Kinases/antagonists & inhibitors/*metabolism MH - Thermogenesis/*physiology PMC - PMC4064112 MID - NIHMS578779 EDAT- 2014/04/22 06:00 MHDA- 2015/06/16 06:00 PMCR- 2015/06/03 CRDT- 2014/04/22 06:00 PHST- 2013/10/25 00:00 [received] PHST- 2014/01/21 00:00 [revised] PHST- 2014/03/13 00:00 [accepted] PHST- 2014/04/22 06:00 [entrez] PHST- 2014/04/22 06:00 [pubmed] PHST- 2015/06/16 06:00 [medline] PHST- 2015/06/03 00:00 [pmc-release] AID - S1550-4131(14)00123-5 [pii] AID - 10.1016/j.cmet.2014.03.018 [doi] PST - ppublish SO - Cell Metab. 2014 Jun 3;19(6):967-80. doi: 10.1016/j.cmet.2014.03.018. Epub 2014 Apr 17.