Obesity is associated with a state of chronic systemic inflammation which has been implicated in the pathogenesis of many co-morbid conditions. Visceral adipose tissue is an important site of inflammation in obesity and is a strong independent risk factor for adverse clinical sequelae and mortality in obese humans. We demonstrate marked increased expression of LIGHT, an understudied but important regulator of inflammation, in visceral compared to subcutaneous adipose tissue from obese humans. Our long-term goals are to elucidate mechanisms of heightened inflammation and insulin resistance in adipose tissue in obesity and to develop therapy for obesity-related systemic inflammation and insulin resistance independent of weight loss. Our short-term goals are to define the role of LIGHT in inflammation and insulin resistance in adipose tissue in human obesity. Our central hypothesis is that increased LIGHT expression by T-cells in visceral adipose tissue in obese humans induces an inflammatory phenotype in tissue macrophages which in turn causes insulin resistance in adipocytes, and that LIGHT blockade will abrogate the inflammatory and diabetogenic properties of tissue macrophages.
Our specific aims will 1. study the expression of and identify the primary cellular sources of LIGHT and related mediators in adipose tissue in obese humans 2. define the role of LIGHT in regulating inflammation in adipose tissue assocaiteed [sic] lymphocytes in vitro, and 3. define the role of LIGHT in regulating insulin resistance in adipocytes in vitro. Relevance: This translational research proposal is significant because it will elucidate mechanisms of inflammation and insulin resistance within adipose tissue in human obesity and determine if manipulation of LIGHT-related molecular pathways attenuates inflammation and insulin resistance in adipocytes. These experiments will guide future research directed towards developing LIGHT-based therapy for obesity-related inflammation, insulin resistance, diabetes and other metabolic sequelae of obesity independent of weight loss. This proposal will provide Dr. Robert O'Rourke with the training necessary to develop into an independent translational research scientist.
|O?rourke, Robert W (2014) Metabolic thrift and the genetic basis of human obesity. Ann Surg 259:642-8|
|Butler, Andrew A; O'Rourke, Robert W (2013) Bariatric surgery in the era of personalized medicine. Gastroenterology 144:497-500|
|O'Rourke, Robert W; Meyer, Kevin A; Gaston, Garen et al. (2013) Hexosamine biosynthesis is a possible mechanism underlying hypoxia's effects on lipid metabolism in human adipocytes. PLoS One 8:e71165|
|Varlamov, Oleg; Chu, Michael P; McGee, Whitney K et al. (2013) Ovarian cycle-specific regulation of adipose tissue lipid storage by testosterone in female nonhuman primates. Endocrinology 154:4126-35|
|O'Rourke, Robert W; Gaston, Garen D; Meyer, Kevin A et al. (2013) Adipose tissue NK cells manifest an activated phenotype in human obesity. Metabolism 62:1557-61|
|O'Rourke, Robert W; Lumeng, Carey N (2013) Obesity heats up adipose tissue lymphocytes. Gastroenterology 145:282-5|
|O'Rourke, Robert W (2013) Inflammation, obesity, and the promise of immunotherapy for metabolic disease. Surg Obes Relat Dis 9:609-16|
|O'Rourke, Robert W; White, Ashley E; Metcalf, Monja D et al. (2012) Systemic inflammation and insulin sensitivity in obese IFN-? knockout mice. Metabolism 61:1152-61|
|Varlamov, Oleg; White, Ashley E; Carroll, Julie M et al. (2012) Androgen effects on adipose tissue architecture and function in nonhuman primates. Endocrinology 153:3100-10|
|Enestvedt, C K; Hosack, L; Hoppo, T et al. (2012) Recombinant vascular endothelial growth factor165 gene therapy improves anastomotic healing in an animal model of ischemic esophagogastrostomy. Dis Esophagus 25:456-64|
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