Novel roles of iRhom2 in the regulation of adiposity and inflammation in diet-induced obesity

Obesity is defined by the excess accumulation of body fat. It is an increasingly common affliction of humans, affecting roughly two billion people worldwide. Chronic low-grade inflammation and a metabolic syndrome characterized by impaired glucose and insulin sensitivity are two of the hallmarks of obesity but the relationship between inflammation and the onset of metabolic syndrome and inflammation is incompletely understood. Murine models of obesity have implicated M1 macrophages and tumor necrosis factor (TNF), but inhibition of TNF alone has failed to mitigate metabolic dysregulation in patients with obesity or diabetes, suggesting that other molecules play a role in the onset of metabolic syndrome. The release of soluble bioactive TNF from TNF-expressing cells is regulated by a disintegrin and metalloproteinase (ADAM) 17 that also controls the release of epidermal growth factor receptor (EGFR) agonists, has been shown to be dysregulated in the adipose tissue of obese patients. Accordingly, the principal objectives of this dissertation have been to further characterize the regulation and role of the mobilization of TNF and EGFR signaling pathways as triggered by a long-term high-fat diet. Key to our experimental approach has been use of a genetic model of ADAM17 inactivity accomplished by deletion (-/-) of its positive regulator, the inactive rhomboid 2 (iRhom2). This dissertation demonstrates that loss of ADAM17 activity in immune cells leads to decreased adipose tissue inflammation, accelerated adiposity, and exacerbated insulin resistance in a murine model of diet-induced obesity. In our model, high-fat diet-induced inflammatory and metabolic responses have been decoupled, demonstrating a novel role for iRhom2 as an immuno-metabolic regulator, affecting adipose tissue inflammation and insulin resistance via distinct molecular mechanisms. In support of this conclusion, in vitro and ex vivo studies demonstrated that effects of initially low levels of diverse inflammatory stimuli (simulating low-grade inflammation induced by highfat diet) can be amplified by iRhom2-dependent extracellular mobilization of TNF that drives sustained autocrine/paracrine activation of TNF signal transduction. Conversely, we observed that the loss of iRhom2-mediated EGFR signaling in mesenchymal stem cells leads to decreased adipocyte lineage commitment which can be rescued by the addition of an exogenous EGFR agonist. In differentiated adipocytes, the loss of EGFR signaling leads to hypertrophy accompanied by dysregulated autophagy and lipid metabolism. Taken together, this dissertation establishes iRhom2 as a novel and multi-potent regulator of adipose tissue inflammation, adiposity, and insulin resistance in a murine model of diet-induced obesity.