The long-term goal of this proposal is to elucidate mechanisms that regulate energy balance. Here, we investigate the regulation of lipid handling and energy homeostasis in adipose tissue with a specific focus on elucidating how signal transduction pathways intersect with metabolic pathways to control thermogenesis and insulin sensitivity. Healthy adipocytes dynamically switch between anabolic and catabolic lipid metabolism upon fluctuations in systemic nutrient availability and thermal stress to support the organism's energetic demands. Maintaining this metabolic flexibility depends upon signals that tightly coordinate de novo fatty acid and triacylglycerol synthesis with lipolysis and fatty acid oxidation. For unclear reasons, overweight or obesity impairs this metabolic flexibility and leads to chronic diseases such as insulin resistance, T2DM, fatty liver disease, cardiovascular disease, and certain cancers. The long-term goal of this research is to understand the molecular basis of how adipocytes sense and respond to nutrients to control energy balance, and how over-nutrition reprograms these signaling circuits to cause disease. The specific objective of this proposal is to elucidate the mechanisms by which the mechanistic target of rapamycin complex 2 (mTORC2), which we previously showed is a key regulator of adipocyte lipid metabolism, links systemic nutrient availability with intracellular metabolic control. To test this, we are taking a multidisciplinary approach utilizing genetically engineered mice, primary cell lines, and pharmacological agents in combination with state-of-the-art proteomics and metabolite profiling to delineate the downstream metabolic circuits under direct and indirect mTORC2 control that are relevant to adipose tissue related diseases. Our previous work on this project revealed that inhibiting mTORC2 in brown adipocytes enhances diet-induced thermogenesis, that inhibiting mTORC2 in white adipose tissue causes severe insulin resistance, that ChREBP is a novel mTORC2 effector that regulates de novo lipogenesis downstream of mTORC2, and that the consequences of mTORC2 loss in brown and white fat are phenotypically similar to the effects of a diabetogenic high fat diet on these tissues. Building upon this knowledge base, we will continue elucidating the mechanisms by which mTORC2 programs adipocyte metabolism in Aim 1, investigate the mechanistic similarities and potential connection between mTORC2 loss and high fat diet on adipocyte metabolism in Aim 2, and investigate a novel transcriptional circuit under direct mTORC2 control that regulates adipocyte lipid metabolism in Aim 3. Elucidating how nutrient-sensing signaling pathways like the mTOR pathway link nutritional signals to metabolic regulation in adipocytes has important implications for advancing therapies to treat obesity, type 2 diabetes, and related metabolic diseases.

Public Health Relevance

The prevalence of metabolic disorders in the United States is escalating, placing significant burden on the U.S. health care system. Overweight and obesity in particular is a major risk factor for type 2 diabetes, dyslipidaemias, cardiovascular disease, and cancer, and is increasing worldwide at epidemic rates. In this proposal, we investigate the molecular basis of metabolic homeostasis, energy expenditure, and insulin resistance focusing on the role of adipose tissue lipid metabolism with the goal of elucidating potential therapeutic strategies to defend against obesity by preventing or reversing insulin resistance.

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)
Program Officer
Haft, Carol R
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University of Massachusetts Medical School Worcester
Anatomy/Cell Biology
Schools of Medicine
United States
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Sanchez-Gurmaches, Joan; Tang, Yuefeng; Jespersen, Naja Zenius et al. (2018) Brown Fat AKT2 Is a Cold-Induced Kinase that Stimulates ChREBP-Mediated De Novo Lipogenesis to Optimize Fuel Storage and Thermogenesis. Cell Metab 27:195-209.e6
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Lee, Peter L; Jung, Su Myung; Guertin, David A (2017) The Complex Roles of Mechanistic Target of Rapamycin in Adipocytes and Beyond. Trends Endocrinol Metab 28:319-339
Cederquist, Carly T; Lentucci, Claudia; Martinez-Calejman, Camila et al. (2017) Systemic insulin sensitivity is regulated by GPS2 inhibition of AKT ubiquitination and activation in adipose tissue. Mol Metab 6:125-137
Sanchez-Gurmaches, Joan; Hung, Chien-Min; Guertin, David A (2016) Emerging Complexities in Adipocyte Origins and Identity. Trends Cell Biol 26:313-326
Lee, Peter L; Tang, Yuefeng; Li, Huawei et al. (2016) Raptor/mTORC1 loss in adipocytes causes progressive lipodystrophy and fatty liver disease. Mol Metab 5:422-32
Tang, Yuefeng; Wallace, Martina; Sanchez-Gurmaches, Joan et al. (2016) Adipose tissue mTORC2 regulates ChREBP-driven de novo lipogenesis and hepatic glucose metabolism. Nat Commun 7:11365
Sanchez-Gurmaches, Joan; Hsiao, Wen-Yu; Guertin, David A (2015) Highly selective in vivo labeling of subcutaneous white adipocyte precursors with Prx1-Cre. Stem Cell Reports 4:541-50
Sanchez-Gurmaches, Joan; Guertin, David A (2014) mTORC1 gRABs the Golgi. Cancer Cell 26:601-3
Hung, Chien-Min; Calejman, Camila Martinez; Sanchez-Gurmaches, Joan et al. (2014) Rictor/mTORC2 loss in the Myf5 lineage reprograms brown fat metabolism and protects mice against obesity and metabolic disease. Cell Rep 8:256-71

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