Regulation of Adipose Tissue Function and Metabolic Homeostasis.

Metabolic syndrome is emerging as a global epidemic that increases the risk for type 2 diabetes, cardiovascular disease, and fatty liver disease. Brown and white adipose tissues carry out diverse metabolic functions and are important for metabolic homeostasis. My thesis work focused on elucidating the mechanisms through which adipocytes regulate their intrinsic cellular function and communicate with other tissues. Chronic low-grade inflammation is emerging as the pathogenic link between obesity and metabolic disease. Persistent immune activation in WAT impairs insulin sensitivity and systemic metabolism in part through the actions of proinflammatory cytokines. Here we identified Otop1 as a component of a counter-inflammatory pathway that is induced in WAT during obesity. Otop1 expression is markedly increased in obese mouse WAT and is stimulated by TNFalpha in cultured adipocytes. Otop1 mutant mice respond to high-fat diet with pronounced insulin resistance and hepatic steatosis, accompanied by augmented adipose tissue inflammation. It also attenuates interferon-gamma signaling through physical interaction with and downregulation of the transcription factor STAT1. Thus, Otop1 defines a unique target of cytokine signaling that attenuates obesity-induced adipose tissue inflammation and plays an adaptive role in maintaining metabolic homeostasis in obesity. Brown fat activates uncoupled respiration to defend against cold and also contributes to systemic metabolism. To date, the metabolic action of brown fat has been primarily attributed to adaptive thermogenesis via uncoupling protein 1. Whether brown fat engages other tissues through secreted proteins remains largely unexplored. Here we show that Nrg4, a member of the EGF family of extracellular ligands, is enriched in brown adipose tissue, highly inducible during brown adipogenesis, and markedly reduced in rodent and human obesity. Gain- and loss-of-function studies in mice demonstrated that Nrg4 protects against diet-induced insulin resistance and hepatic steatosis through attenuating lipogenic signaling in the liver. Mechanistically, Nrg4 stimulates ErbB3/ErbB4 signaling in hepatocytes and negatively regulates de novo lipogenesis mediated by LXR/SREBP1c in a cell-autonomous manner. These results establish Nrg4 as a brown fat-enriched adipokine with therapeutic potential for the treatment of type 2 diabetes and non-alcoholic fatty liver disease.PhDCellular & Molecular BiologyUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/107321/1/gracewgx_1.pd