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

Authors: Liu, Meilian  Bai, Juli  He, Sijia  Villarreal, Ricardo  Hu, Derong  Zhang, Chuntao  Yang, Xin  Liang, Huiyun  Slaga, Thomas J  Yu, Yonghao  Zhou, Zhiguang  Blenis, John  Scherer, Philipp E  Dong, Lily Q  Liu, Feng 
Citation: Liu M, etal., Cell Metab. 2014 Jun 3;19(6):967-80. doi: 10.1016/j.cmet.2014.03.018. Epub 2014 Apr 17.
Pubmed: (View Article at PubMed) PMID:24746805
DOI: Full-text: DOI:10.1016/j.cmet.2014.03.018

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.


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RGD Object Information
RGD ID: 13673757
Created: 2018-06-23
Species: All species
Last Modified: 2018-06-23
Status: ACTIVE


RGD is funded by grant HL64541 from the National Heart, Lung, and Blood Institute on behalf of the NIH.