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

• 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
• 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

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.

米色脂肪细胞通过将化学能转化为热量来燃烧脂肪，被认为是对抗肥胖的新的治疗靶点。第2组先天淋巴样细胞（ILC 2）最近被证明存在于脂肪组织中，并通过产生2型细胞因子IL-5和IL-13以及促进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，增加的ILC 2反应限制了肥胖的发展。然而，招募和激活脂肪居民ILC 2的潜在机制在很大程度上仍然未知。我们的初步研究确定脂联素是ILC 2的关键调节因子。同时，脂联素在体内和体外抑制ILC 2以及ILC 2活化的下游事件，包括IL-4和IL-13途径、M2巨噬细胞活化和去甲肾上腺素产生。此外，脂联素基因敲除小鼠表现出基础、急性和慢性冷诱导的能量消耗增加以及白色脂肪变黑，而脂联素受体激动剂adipoRon的给药抑制了这一点。这些数据表明，脂联素具有抗生热功能。此外，ILC 2的缺乏减少了体外IL-4/13途径和UCP 1的脂肪抑制。综上所述，我们的数据表明，脂联素抑制白色脂肪组织的布朗宁，这种作用是通过抑制ILC 2的功能介导的。我们将首先确定脂联素是否通过抑制ILC 2依赖性IL-4/13途径抑制WAT的布朗宁。接下来，我们将描述脂联素调节ILC 2功能的分子机制。这项研究将阐明脂联素作为脂肪组织中ILC 2的关键调节因子的新作用。阐明参与白色脂肪布朗宁的潜在信号传导机制以及脂肪细胞与脂肪驻留ILC 2之间的相互作用可能揭示新的有希望的抗肥胖药物靶点，并导致肥胖相关代谢疾病的新治疗方法。