Grb10 Promotes Lipolysis and Thermogenesis by Phosphorylation-Dependent Feedback Inhibition of mTORC1

被引:104
|
作者
Liu, Meilian [1 ,2 ,3 ]
Bai, Juli [1 ,2 ,3 ]
He, Sijia [1 ,2 ,3 ]
Villarreal, Ricardo [4 ]
Hu, Derong [1 ]
Zhang, Chuntao [1 ,5 ]
Yang, Xin [4 ]
Liang, Huiyun [4 ]
Slaga, Thomas J. [1 ]
Yu, Yonghao [6 ]
Zhou, Zhiguang [2 ,3 ]
Blenis, John [6 ]
Scherer, Philipp E. [7 ,8 ]
Dong, Lily Q. [4 ]
Liu, Feng [1 ,2 ,3 ]
机构
[1] Univ Texas Hlth Sci Ctr San Antonio, Dept Pharmacol, San Antonio, TX 78229 USA
[2] Cent S Univ, Xiangya Hosp 2, Minist Educ, Metab Syndrome Res Ctr, Changsha 410011, Hunan, Peoples R China
[3] Cent S Univ, Xiangya Hosp 2, Minist Educ, Diabet Ctr,Key Lab Diabet Immunol, Changsha 410011, Hunan, Peoples R China
[4] Univ Texas Hlth Sci Ctr San Antonio, Dept Cellular & Struct Biol, San Antonio, TX 78229 USA
[5] Xinjiang Med Univ, Sch Basic Med, Dept Microbiol, Urumqi 830011, Xinjiang, Peoples R China
[6] Harvard Univ, Sch Med, Dept Cell Biol, Boston, MA 02115 USA
[7] Univ Texas SW Med Ctr Dallas, Dept Internal Med, Touchstone Diabet Ctr, Dallas, TX 75390 USA
[8] Univ Texas SW Med Ctr Dallas, Dept Cell Biol, Dallas, TX 75390 USA
关键词
INSULIN-RECEPTOR SUBSTRATE-1; PPAR-GAMMA ACTIVATION; DIET-INDUCED OBESITY; FACTOR-I RECEPTORS; BROWN ADIPOCYTES; ADIPOSE-TISSUE; MAMMALIAN TARGET; WHITE FAT; ADIPONECTIN MULTIMERIZATION; RAPAMYCIN PATHWAY;
D O I
10.1016/j.cmet.2014.03.018
中图分类号
Q2 [细胞生物学];
学科分类号
071009 ; 090102 ;
摘要
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.
引用
收藏
页码:967 / 980
页数:14
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