Group 2 innate lymphoid cells promote beiging of white adipose tissue and limit obesity

摘要

免疫系统现在被认为与遗传因素和环境因素一起涉及到肥胖的形成中。最新研究发现，脂肪组织中的"2-组先天淋巴样细胞"(ILC2S)是造成小鼠发生肥胖的一个因素。David Artis及同事在这项研究中显示，ILC2s通过响应于白介素-33生成"蛋氨酸-脑啡肽"肽在能量平衡中扮演一个关键角色。这会促进米黄色脂肪细胞(从白色脂肪组织出现的一个专门化的脂肪细胞群)的出现。这一"米黄色化"过程导致能量消耗增加和脂肪堆积减少。%Obesity is an increasingly prevalent disease regulated by genetic and environmental factors. Emerging studies indicate that immune cells, including monocytes, granulocytes and lymphocytes, regulate metabolic homeostasis and are dysregulated in obesity. Group 2 innate lymphoid cells (ILC2s) can regulate adaptive immunity and eosinophil and alternatively activated macrophage responses, and were recently identified in murine white adipose tissue (WAT) where they may act to limit the development of obesity. However, ILC2s have not been identified in human adipose tissue, and the mechanisms by which ILC2s regulate metabolic homeostasis remain unknown. Here we identify ILC2s in human WAT and demonstrate that decreased ILC2 responses in WAT are a conserved characteristic of obesity in humans and mice. Interleukin (IL)-33 was found to be critical for the maintenance of ILC2s in WAT and in limiting adiposity in mice by increasing caloric expenditure. This was associated with recruitment of uncoupling protein 1 (UCP1)~+ beige adipocytes in WAT, a process known as beiging or browning that regulates caloric expenditure. IL-33-induced beiging was dependent on ILC2s, and IL-33 treatment or transfer of IL-33-elicited ILC2s was sufficient to drive beiging independently of the adaptive immune system, eosinophils or IL-4 receptor signalling. We found that ILC2s produce methionine-enkephalin peptides that can act directly on adipocytes to upregulate Ucp1 expression in vitro and that promote beiging in vivo. Collectively, these studies indicate that, in addition to responding to infection or tissue damage, ILC2s can regulate adipose function and metabolic homeostasis in part via production of enkephalin peptides that elicit beiging.