Obesity is a public health epidemic wordwide and affects nearly a third of adult Americans. Several devastating co-morbidities are associated with obesity, including insulin resistance/type II diabetes and non-alcoholic steatohepatitis/non-alcoholic fatty liver disease. Paradoxically, in obese states, lipid storage is not suppressed, in spite of resistance to insulin action. This ?nding that has important consequences for the management of obesity and its complications. An emerging molecular mechanism linking obesity to excessive lipid storage is the mTORC1/SREBP1c pathway, which our group and others have identi?ed as both activated with obesity, and as a key regulator of lipogenesis and new adipocyte formation. This study will test the hypothesis that mTORC1 activation in the obese state elevates lipid levels, due to activation of both adipogenesis and lipogenesis. To accomplish this, we have developed several new innovative models to test speci?c aspects of this hypothesis. First, we have generated adipose-speci?cTsc1 knockout mice as a model of chronic adipose mTORC1 activation. The chronic elevations in mTORC1 signaling in these mice are associated with elevated fat mass and increased hepatic steatosis, likely due to enhanced de novo lipogenesis in adipose tissue. We will determine the molecular changes resulting from chronic mTORC1 elevation, and identify the molecular mechanisms underlying these mTORC1-dependent increases in lipid storage. Elevated adiposity may is caused by increased adipogenesis, so we will determine the molecular mechanisms by which mTORC1 positively regulates adipogenesis. We will speci?cally evaluate the hypothesis that mTORC1 regulates PPAR? mRNA stability via a miRNA-dependent mechanism. To test the role of mTORC1 in the liver, we will study both activation and inhibition this kinase via ablation of the essential mTORC1 component Rptor, and Tsc1 respectively in adult mouse livers. This approach will allow us to evaluate whether mTORC1 is necessary and suf?cient for the development and maintenance of hepatic steatosis in adult liver tissues for the ?rst time. This is an important gp in our knowledge, since in obesity-associated liver disease, mTORC1 is not activated during development, but co-incident with elevations in adiposity. We will explore the physiological signi?cance of a positive feedback loop in SREBP1c using genome-edited rats. This key mTORC1 target plays an important role in de novo lipogenesis and the ampli?cation of SREBP1c action by a transcriptional feed-forward circuit has been proposed to be an important component of both diet-induced hepatic steatosis and obesity. By deleting only the relevant SRE at the endogenous Srebf1 locus, we can test the importance of this circuit in a controlled and direct manner. Importantly, these rats will also allow us to separate the direct activation of SREBP1c by mTORC1 and other signals, from the confounding effects of positive feedback. Together these studies will answer fundamental mechanistic questions regarding how mTORC1 and SREBP1c regulate adipogenesis and lipogenesis, providing insights into potential routes of therapeutic intervention for obesity and liver disease.

Public Health Relevance

Obesity is a major epidemic, and is the leading cause of liver disease and type II diabetes. This study will examine how nutrient sensing pathways regulate, and can alleviate excessive weight gain and its associated complications.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
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Integrative Nutrition and Metabolic Processes Study Section (INMP)
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Silva, Corinne M
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University of Tennessee Health Science Center
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McAllan, Liam; Maynard, Kristen R; Kardian, Alisha S et al. (2018) Disruption of brain-derived neurotrophic factor production from individual promoters generates distinct body composition phenotypes in mice. Am J Physiol Endocrinol Metab :
Urraca, Nora; Hope, Kevin; Victor, A Kaitlyn et al. (2018) Significant transcriptional changes in 15q duplication but not Angelman syndrome deletion stem cell-derived neurons. Mol Autism 9:6
Wilson, Matthew J; Sen, Ananda; Bridges, Dave et al. (2018) Higher baseline expression of the PTGS2 gene and greater decreases in total colonic fatty acid content predict greater decreases in colonic prostaglandin-E2 concentrations after dietary supplementation with ?-3 fatty acids. Prostaglandins Leukot Essent Fatty Acids 139:14-19
Harvey, Innocence; Stephenson, Erin J; Redd, JeAnna R et al. (2018) Glucocorticoid-Induced Metabolic Disturbances Are Exacerbated in Obese Male Mice. Endocrinology 159:2275-2287
Dong, Qingming; Kuefner, Michael S; Deng, Xiong et al. (2018) Sex-specific differences in hepatic steatosis in obese spontaneously hypertensive (SHROB) rats. Biol Sex Differ 9:40
Ponnusamy, Suriyan; Tran, Quynh T; Thiyagarajan, Thirumagal et al. (2017) An estrogen receptor ?-selective agonist inhibits non-alcoholic steatohepatitis in preclinical models by regulating bile acid and xenobiotic receptors. Exp Biol Med (Maywood) 242:606-616
Bridges, Dave (2017) Weight loss effects of methotrexate and cyclophosphamide. Oncotarget 8:5640
Ponnusamy, Suriyan; Tran, Quynh T; Harvey, Innocence et al. (2017) Pharmacologic activation of estrogen receptor ? increases mitochondrial function, energy expenditure, and brown adipose tissue. FASEB J 31:266-281
Ponnusamy, Suriyan; Sullivan, Ryan D; You, Dahui et al. (2017) Androgen receptor agonists increase lean mass, improve cardiopulmonary functions and extend survival in preclinical models of Duchenne muscular dystrophy. Hum Mol Genet 26:2526-2540
Kuefner, Michael S; Pham, Kevin; Redd, Jeanna R et al. (2017) Secretory phospholipase A2 group IIA modulates insulin sensitivity and metabolism. J Lipid Res 58:1822-1833

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