Adipose tissues play key roles in the storage, release, and dispersal of highly energetic molecules to maintain energy homeostasis of the organism in response to environmental and hormonal stimuli. Adipose tissue dysfunction is associated with obesity and various metabolic diseases. Our preliminary studies showed that fat-specific knockout of the Growth factor receptor binding protein-10 (Grb10) in mice substantially increased mTORC1 signaling, greatly promoted adiposity and the conversion of BAT to a WAT-like tissue, drastically suppressed the expression of uncoupling protein 1 (UCP1) and energy expenditure, and significantly enhanced high fat diet (HFD)-induced insulin resistance. Based on these findings, we hypothesize that Grb10 regulates lipid metabolism and thermogenic activity in adipose tissues by feedback regulation of mTORC1. To test this hypothesis, we will first characterize the roles of Grb10 in the regulation of lipid metabolism and thermogenesis in vivo. We will then determine whether inhibiting the mTORC1 signaling pathway provides a mechanism by which Grb10 regulates lipid metabolism and thermogenic function in adipose tissues. Lastly, we will elucidate the molecular mechanism by which Grb10 negatively regulates mTORC1 signaling in adipocytes. Our study will identify a new important regulator of lipid metabolism and thermogenesis in adipose tissues. The study will also provide new insights into the signaling mechanisms underlying the browning effect in WAT in response to cold and adrenergic stimulation. Identification of Grb10 as a critical regulator of adipocyte function and elucidating the underlying signaling mechanisms may reveal promising new anti-obesity drug targets and lead to novel therapeutic approaches for obesity- associated metabolic diseases.

Public Health Relevance

Adipose tissue dysfunction is associated with obesity and various metabolic diseases, yet the underlying mechanisms remain elusive. The proposed study is to determine the mechanisms regulating lipid biosynthesis and thermogenic gene expression. Results from this study may lead to the development of new therapeutic strategies to prevent obesity-associated metabolic diseases such as type 2 diabetes.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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Cellular Aspects of Diabetes and Obesity Study Section (CADO)
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Haft, Carol R
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University of Texas Health Science Center
Schools of Medicine
San Antonio
United States
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Meng, Wen; Liang, Xiuci; Chen, Hongzhi et al. (2017) Rheb Inhibits Beiging of White Adipose Tissue via PDE4D5-Dependent Downregulation of the cAMP-PKA Signaling Pathway. Diabetes 66:1198-1213
Hu, Fang; Xu, Yong; Liu, Feng (2016) Hypothalamic roles of mTOR complex I: integration of nutrient and hormone signals to regulate energy homeostasis. Am J Physiol Endocrinol Metab 310:E994-E1002
Ruan, Hong; Liu, Feng (2016) Regulation of energy metabolism and maintenance of metabolic homeostasis: the adiponectin story after 20 years. J Mol Cell Biol 8:91-2
Cai, Huan; Dong, Lily Q; Liu, Feng (2016) Recent Advances in Adipose mTOR Signaling and Function: Therapeutic Prospects. Trends Pharmacol Sci 37:303-317
Ou, Xiang; Liu, Meilian; Luo, Hairong et al. (2014) Ursolic acid inhibits leucine-stimulated mTORC1 signaling by suppressing mTOR localization to lysosome. PLoS One 9:e95393
Zhang, Jingjing; Liu, Feng (2014) Tissue-specific insulin signaling in the regulation of metabolism and aging. IUBMB Life 66:485-95
Liu, Meilian; Bai, Juli; He, Sijia et al. (2014) Grb10 promotes lipolysis and thermogenesis by phosphorylation-dependent feedback inhibition of mTORC1. Cell Metab 19:967-80
Liu, Bilian; Liu, Feng (2014) Feedback regulation of mTORC1 by Grb10 in metabolism and beyond. Cell Cycle 13:2643-4