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

脂联素在调节 2 组先天淋巴细胞和脂肪褐变中的作用

基本信息

批准号：
10091038
负责人：
Meilian Liu
金额：
$ 6.06万
依托单位：
UNIVERSITY OF NEW MEXICO HEALTH SCIS CTR
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-07-20 至 2022-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10091038
关键词：
Acute Adipocytes Adipose tissue Adrenergic Agents Agonist Anti-Obesity Agents Antidiabetic Drugs Attention Biology Brown Fat Cell physiology Chemicals Chronic Coupled Data Development Drug Targeting Energy Metabolism Event Exhibits Fatty acid glycerol esters Gene Expression Goals Hand IL4 gene Immune response Immunity In Vitro Indirect Calorimetry Infiltration Insulin Resistance Interleukin-13 Interleukin-4 Interleukin-5 Interleukin-7 Knock-out Knockout Mice Lead Leptin Lipids Lymphoid Cell Macrophage Activation Mediating Metabolic Diseases Modeling Molecular Myelogenous NF-kappa B Norepinephrine Obesity Pathway interactions Physiological Play Production Publishing Regulation Reporting Research Role STAT protein Signal Transduction System Temperature Testing Thermogenesis Time Transgenic Mice adipocyte differentiation adipokines adiponectin base cytokine diabetic in vivo interleukin-13 receptor macrophage metabolic phenotype new therapeutic target novel novel therapeutic intervention obesity development obesity treatment receptor recruit response therapeutic target uncoupling protein 1

项目摘要

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.

米色（或棕色）脂肪细胞通过将化学能转化为热量来燃烧脂质，并已被认为是对抗肥胖的新治疗靶点。最近显示，第 2 组先天淋巴细胞 (ILC2) 存在于脂肪组织中，并通过产生 2 型细胞因子 IL-5 和 IL-13 并促进 IL-4/IL-13 驱动，在调节米色脂肪发育中发挥关键作用2型免疫。此外，ILC2反应的增加限制了肥胖的发展。然而，脂肪驻留 ILC2 的募集和激活背后的机制仍然很大程度上未知。我们的初步研究确定脂联素是 ILC2 的关键调节因子。同时，脂联素在体内和体外抑制 ILC2 以及 ILC2 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产生。此外，脂联素 KO 小鼠表现出基础、急性和慢性寒冷诱导的能量消耗增加以及白色脂肪呈米色，而注射脂联素受体激动剂 adipoRon 可以抑制这种情况。这些数据表明脂联素发挥抗生热功能。此外，体外 ILC2 的缺失会减弱 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，并且这种作用是通过抑制 ILC2 的功能来介导的。我们将首先确定脂联素是否通过抑制 ILC2 依赖性 IL-4/13 途径来抑制 WAT 褐变。接下来，我们将描述脂联素调节 ILC2 功能的分子机制。这项研究将阐明脂联素作为脂肪组织中 ILC2 关键调节因子的新作用。阐明白色脂肪褐变以及脂肪细胞与脂肪驻留 ILC2 之间相互作用的潜在信号机制可能会揭示新的有前景的抗肥胖药物靶点，并为肥胖相关代谢疾病带来新的治疗方法。