Beige (or brite) adipocytes burn lipid by dissipating chemical energy to heat, and have been considered as a new therapeutic target to counteract obesity. Group 2 innate lymphoid cells (ILC2s) were recently shown to be present in adipose tissue and play a critical role in regulating beige fat development by producing type 2 cytokine IL-5 and IL-13 and promoting IL-4/IL-13-driven type 2 immunity. Moreover, increased ILC2 response limits the development of obesity. However, the mechanisms underlying the recruitment and activation of adipose resident ILC2s remains largely unknown. Our preliminary studies identified adiponectin as a key regulator of ILC2. Concurrently, adiponectin suppresses ILC2s, as well as downstream events of ILC2s activation including IL-4 and IL-13 pathway, M2 macrophage activation and norepinephrine production in vivo and in vitro. In addition, adiponectin KO mice display increased basal, acute and chronic cold-induced energy expenditure as well as beigeing of white fat, which was suppressed by administration of the adiponectin receptor agonist adipoRon. These data suggest that adiponectin exerts anti-thermogenic function. Furthermore, absence of ILC2s diminishes adipoRon suppression of IL-4/13 pathway and UCP1 in vitro. Taken together, our data suggest that adiponectin inhibits the browning of white adipose tissue, and this effect is mediated by suppressing the function of ILC2s. We will first determine whether adiponectin suppresses the browning of WAT by inhibiting the ILC2-dependent IL-4/13 pathway. Next, we will characterize the molecular mechanism by which adiponectin regulates the function of ILC2s. This study will elucidate a novel role for adiponectin as a key regulator of ILC2s in adipose tissue. Elucidation of the underlying signaling mechanisms involved in the browning of white fat and interaction between adipocytes and adipose-resident ILC2s may reveal new promising anti-obesity drug targets and lead to novel therapeutic approaches for obesity-associated metabolic diseases.
Brown and Beige (or brite) adipocytes in adipose tissue have strong anti-obesity and anti-diabetic benefits. Adipose-specific type 2 immune response, which is characterized by infiltration of group 2 innate lymphoid cells (ILC2s) and activation of IL-4 and IL-13 pathway, plays a critical role in regulating beige adipocyte development and activation (referred to as browning of white adipose tissue (WAT)) as well as energy expenditure. However, the mechanisms underlying the regulation of type 2 immunity in adipose tissue remains largely unknown. This proposed study will delineate the role of adiponectin in regulating ILC2-driven type 2 immunity and beige adipocyte development in white adipose tissue. The results from this study will lead to identification of the potential therapeutic targets for the treatment of obesity and its associated metabolic diseases.
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