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Cell Metab. 2014 Jun 3;19(6):967-80. doi: 10.1016/j.cmet.2014.03.018. Epub 2014 Apr 17.

Grb10 promotes lipolysis and thermogenesis by phosphorylation-dependent feedback inhibition of mTORC1.

Author information

1
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.
2
Department of Cellular and Structural Biology, University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Drive, San Antonio, TX 78229, USA.
3
Department of Pharmacology, University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Drive, San Antonio, TX 78229, USA.
4
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.
5
Department of Cell Biology, Harvard Medical School, 240 Longwood Avenue, Boston, MA 02115, USA.
6
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.
7
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.
8
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.

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.

PMID:
24746805
PMCID:
PMC4064112
DOI:
10.1016/j.cmet.2014.03.018
[Indexed for MEDLINE]
Free PMC Article

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