@article{2822eef63c084c00a44c3995dda449d0,
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.",
author = "Meilian Liu and Juli Bai and Sijia He and Ricardo Villarreal and Derong Hu and Chuntao Zhang and Xin Yang and Huiyun Liang and Slaga, {Thomas J.} and Yonghao Yu and Zhiguang Zhou and John Blenis and Scherer, {Philipp E.} and Dong, {Lily Q.} and Feng Liu",
note = "Funding Information: We are grateful to Drs. Nicole Nemetz (Laboratory of Animal Resource, UTHSCSA) and Holly Van Remmen (Department of Cellular & Structural Biology, UTHSCSA) for their kind help with the telemetry study. We also thank Dr. Milena Girotti and Ms. Jennifer Donegan from Dr. David Morilak{\textquoteright}s laboratory (Department of Pharmacology, UTHSCSA) for providing fat tissues from cold-stressed rats. This work was supported by NIH RO1 grant DK100697 and grants from the National Nature Science Foundation of China (81130015) and the National Basic Research Program of China (2014CB910500) (to F.L.); an ADA Junior Faculty Award (1-13-JF-37) and an AHA Beginning in Aid Award (11BGIA7620074) (to M.L.); NIH RO1 grants DK69930 (to L.Q.D.), GM51405 (to J.B.), and DK55758, DK099110, and P01-DK088761 (to P.E.S.); an ACRCF (to H.L.); and a CTRC P30 (to T.J.S.). ",
year = "2014",
month = jun,
day = "3",
doi = "10.1016/j.cmet.2014.03.018",
language = "English (US)",
volume = "19",
pages = "967--980",
journal = "Cell Metabolism",
issn = "1550-4131",
publisher = "Cell Press",
number = "6",
}