β2AR regulation of WAT ILC2-mediated metabolic homeostasis

Weill Medical Coll Of Cornell Univ, New York NY

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Abstract

? DESCRIPTION (provided by applicant): Obesity, a metabolic disorder characterized by excess accumulation of adipose tissue, is associated with the development of numerous diseases such as Type 2 diabetes, cardiovascular disease, and colon cancer. Consequently, understanding the pathways involved in the development of obesity is critical to develop strategies for the prevention and treatment of this disease and co-morbidities. White adipose tissue (WAT) in humans and mice is populated by numerous immune cell types, including a recently identified population of group 2 innate lymphoid cells (ILC2s), which critically regulate WAT homeostasis by producing cytokines that modulate systemic metabolic homeostasis and energy expenditure. These findings suggest that immune cells can contribute to the development of obesity, though how the immune system regulates metabolic homeostasis remains poorly defined. Our preliminary studies show that ILC2 depletion is associated with increased weight gain and insulin resistance in mice fed a high-fat diet (HFD), suggesting that ILC2s may negatively regulate the development of obesity. However, pathways controlling ILC2 regulation and function in the context of pathogenic obesity remain unclear. Type 2 inflammation, mediated by ILC2s, is associated with suppression of the ?2AR-dependent sympathetic nervous system, and this pathway has been targeted therapeutically to treat chronic diseases associated with ILC2 responses. Importantly, our preliminary data reveal that human and murine ILC2s express ?2AR and that ?2AR is a direct negative inhibitor of ILC2 responses in the intestine. We therefore hypothesize that the ?2AR pathway negatively regulates WAT ILC2- mediated metabolic homeostasis, which induces weight gain in response to stress, thereby promoting the development of obesity. In the proposed research, we will investigate the role of the ?2AR pathway in human and murine WAT ILC2 development, function, and regulation of metabolic homeostasis. In addition to providing new insights into the pathways controlling WAT ILC2 regulation and function, results from these studies will assess the potential of modulating the ?2AR pathway using existing therapies to promote WAT ILC2-mediated metabolic homeostasis, and may enhance the development of more effective strategies to treat pathogenic obesity.