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

Cell Metab. 2014 Jun 3;19(6):967-80. doi: 10.1016/j.cmet.2014.03.018. Epub 2014 Apr 17.

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 types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / metabolism
  • Adipose Tissue, Brown / metabolism
  • Adipose Tissue, White / metabolism
  • Animals
  • Antibiotics, Antineoplastic / pharmacology
  • Cells, Cultured
  • Cold Temperature
  • Cold-Shock Response
  • Diabetes Mellitus
  • Energy Metabolism / physiology*
  • Feedback, Physiological
  • GRB10 Adaptor Protein / biosynthesis
  • GRB10 Adaptor Protein / metabolism*
  • Insulin Resistance
  • Lipolysis / physiology*
  • Mechanistic Target of Rapamycin Complex 1
  • Mice
  • Mice, Knockout
  • Multiprotein Complexes / antagonists & inhibitors
  • Multiprotein Complexes / metabolism*
  • Obesity
  • Phosphatidylinositol 3-Kinases
  • Phosphorylation
  • Protein Binding
  • Proto-Oncogene Proteins c-akt
  • Receptor, Insulin / metabolism
  • Regulatory-Associated Protein of mTOR
  • Signal Transduction / physiology
  • Sirolimus / pharmacology
  • TOR Serine-Threonine Kinases / antagonists & inhibitors
  • TOR Serine-Threonine Kinases / metabolism*
  • Thermogenesis / physiology*

Substances

  • Adaptor Proteins, Signal Transducing
  • Antibiotics, Antineoplastic
  • Grb10 protein, mouse
  • Multiprotein Complexes
  • Regulatory-Associated Protein of mTOR
  • Rptor protein, mouse
  • GRB10 Adaptor Protein
  • Phosphatidylinositol 3-Kinases
  • TOR Serine-Threonine Kinases
  • Receptor, Insulin
  • Mechanistic Target of Rapamycin Complex 1
  • Proto-Oncogene Proteins c-akt
  • Sirolimus