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

Meilian Liu, Juli Bai, Sijia He, Ricardo Villarreal, Derong Hu, Chuntao Zhang, Xin Yang, Huiyun Liang, Thomas J. Slaga, Yonghao Yu, Zhiguang Zhou, John Blenis, Philipp E. Scherer, Lily Q. Dong, Feng Liu

Research output: Contribution to journalArticlepeer-review

56 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)967-980
Number of pages14
JournalCell Metabolism
Volume19
Issue number6
DOIs
StatePublished - Jun 3 2014

ASJC Scopus subject areas

  • Physiology
  • Molecular Biology
  • Cell Biology

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