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

doi:10.1016/j.cmet.2014.03.018

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.

Authors

Meilian Liu¹, Juli Bai¹, Sijia He¹, Ricardo Villarreal², Derong Hu³, Chuntao Zhang⁴, Xin Yang², Huiyun Liang², Thomas J Slaga³, Yonghao Yu⁵, Zhiguang Zhou⁶, John Blenis⁵, Philipp E Scherer⁷, Lily Q Dong², Feng Liu⁸

Affiliations

¹ Department of Pharmacology, University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Drive, San Antonio, TX 78229, USA; Metabolic Syndrome Research Center and Diabetes Center, Key Laboratory of Diabetes Immunology, Ministry of Education, Second Xiangya Hospital, Central South University, 139 Middle Renmin Road, Changsha, Hunan 410011, China.
² Department of Cellular and Structural Biology, University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Drive, San Antonio, TX 78229, USA.
³ Department of Pharmacology, University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Drive, San Antonio, TX 78229, USA.
⁴ Department of Pharmacology, University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Drive, San Antonio, TX 78229, USA; The Department of Microbiology, School of Basic Medicine, Xinjiang Medical University, 393 Xinyi Road, Urumqi, Xinjiang 830011, China.
⁵ Department of Cell Biology, Harvard Medical School, 240 Longwood Avenue, Boston, MA 02115, USA.
⁶ Metabolic Syndrome Research Center and Diabetes Center, Key Laboratory of Diabetes Immunology, Ministry of Education, Second Xiangya Hospital, Central South University, 139 Middle Renmin Road, Changsha, Hunan 410011, China.
⁷ Touchstone Diabetes Center, Department of Internal Medicine, and Department of Cell Biology, UT Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390-8549, USA.
⁸ Department of Pharmacology, University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Drive, San Antonio, TX 78229, USA; Metabolic Syndrome Research Center and Diabetes Center, Key Laboratory of Diabetes Immunology, Ministry of Education, Second Xiangya Hospital, Central South University, 139 Middle Renmin Road, Changsha, Hunan 410011, China. Electronic address: [email protected].

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
Receptor, Insulin
Mechanistic Target of Rapamycin Complex 1
Proto-Oncogene Proteins c-akt
TOR Serine-Threonine Kinases
Sirolimus

Abstract

Publication types

MeSH terms

Substances

Grants and funding