Grb10 promotes lipolysis and thermogenesis by phosphorylation-dependent feedback inhibition of mTORC1 Academic Article uri icon

Overview

MeSH Major

  • Energy Metabolism
  • GRB10 Adaptor Protein
  • Lipolysis
  • Multiprotein Complexes
  • TOR Serine-Threonine Kinases
  • Thermogenesis

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.

publication date

  • June 3, 2014

Research

keywords

  • Academic Article

Identity

Language

  • eng

PubMed Central ID

  • PMC4064112

Digital Object Identifier (DOI)

  • 10.1016/j.cmet.2014.03.018

PubMed ID

  • 24746805

Additional Document Info

start page

  • 967

end page

  • 80

volume

  • 19

number

  • 6