Obesity in Mice Type 2 and Type II NKT Cells That Regulate Cutting Edge: IL-25 Elicits Innate Lymphoid

The cellular composition of visceral adipose tissue (VAT) and release of cytokines by such cells within VAT has been implicated in regulating obesity and metabolic homeostasis. We show the importance of IL-25– responsive innate cells, which release the Th2 cytokine IL-13, in regulating weight and glucose homeostasis in mouse models of diet-induced obesity. Treating obese mice with IL-25 induces weight loss and improves glucose tolerance, and is associated with increased infiltration of innate lymphoid type 2 cells (ILC2), type I and type II NKT cells, eosinophils, and alternatively activated macrophages into the VAT. By depleting ILC2 in obese Rag1 2/2 mice, we observe exacerbated weight gain and glucose intolerance. Conversely, transferring ILC2 or type I or type II NKT cells into obese mice induces transient weight loss and stabilizes glucose homeostasis. Our data identify a mechanism whereby IL-25 eliciting IL-13–producing innate cells regulates inflammation in adipose tissue and prevents diet-induced obesity. A hallmark of obesity is chronic low-grade inflammation that has a pivotal role in the progression to metabolic disorders, such as atherosclerosis and type 2 diabetes. The inflammatory cell composition of adipose tissue can profoundly influence the regulation of weight and the maintenance of metabolic homeostasis. Although there is a range of resident populations of immune cells in vis-ceral adipose tissue (VAT), such as eosinophils, effector and memory T cells, regulatory T cells, and NKT cells, there is also a marked macrophage infiltration that is further increased in VAT of obese individuals (1). The polarization of macrophages within VAT to classically activated (CAM) or alternatively activated macrophages (AAMs) influences metabolic hemostasis; in the VAT of lean individuals, AAMs predominate , whereas obesity leads to a CAM-dominated infiltration of the VAT (2). The cells in VAT that release cytokines that initiate the polarization of macrophages to a CAM (INF-g, IL-6, or TNF-a) or AAM (IL-4 and IL-13) profile are not fully elucidated. Although studies into homeostatic glucose regulation have outlined the importance of AAM in promoting insulin sensitivity , eosinophils have been shown to be important in sustaining AAM in the VAT of mice on high-fat diet (HFD), by the localized release of IL-4 and IL-13 (3). More recently, attention has focused on the role of innate lymphoid cell (ILC) types that are present in the VAT, in particular, type 2 ILC. Interestingly, one such ILC2 population was identified in fat-associated lymphoid clusters in both mice and humans (4). A …