The Role of Adiponectin in Regulating Group 2 Innate Lymphoid Cells and Browning in Fat

米色(或褐褐色)脂肪细胞通过消耗化学能加热来燃烧脂肪，被认为是对抗肥胖的新的治疗靶点。第二组天然淋巴样细胞(ILC2s)最近被发现存在于脂肪组织中，通过产生2型细胞因子IL-5和IL-13，促进IL-4/IL-13驱动的2型免疫，在调节米色脂肪发育中发挥关键作用。此外，ILC2反应的增加限制了肥胖的发展。然而，招募和激活脂肪驻留的ILC2的潜在机制在很大程度上仍然不清楚。我们的初步研究证实脂联素是ILC2的关键调节因子。同时，脂联素在体内和体外抑制ILC2s，以及ILC2s激活的下游事件，包括IL-4和IL-13途径，M2巨噬细胞激活和去甲肾上腺素的产生。此外，脂联素KO小鼠表现出基础、急性和慢性冷诱导的能量消耗增加以及白色脂肪褐变，这一现象可被脂联素受体激动剂AdipoRon抑制。这些数据表明，脂联素具有抗发热作用。此外，在体外，ILC2s的缺失减弱了AdipoRon对IL-4/13途径和UCP1的抑制。综上所述，我们的数据表明，脂联素抑制白色脂肪组织的褐变，这种作用是通过抑制ILC2s的功能来实现的。我们将首先确定脂联素是否通过抑制ILC2依赖的IL-4/13途径来抑制WAT的褐变。接下来，我们将描述脂联素调节ILC2s功能的分子机制。这项研究将阐明脂联素作为脂肪组织中ILC2s的关键调节因子的新作用。阐明白色脂肪褐变的潜在信号机制以及脂肪细胞与脂肪驻留的ILC2之间的相互作用可能会揭示新的抗肥胖药物靶点，并导致肥胖相关代谢性疾病的新治疗方法。

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.