β2AR regulation of WAT ILC2-mediated metabolic homeostasis

WAT ILC2 介导的代谢稳态的 β2AR 调节

• 批准号: 9121980
• 负责人: Naomi Ava Yudanin
• 金额: $ 5.25万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-04-01 至 2019-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9121980
• 关键词: Address; Adipose tissue; Adult; Affect; Amphiregulin; Cardiovascular Diseases; Cells; Chronic Disease; Colon; Colon Carcinoma; Comorbidity; Cytokine Receptors; Data; Development; Disease; Energy Metabolism; Exhibits; Functional disorder; Glucose; Healthcare Systems; High Fat Diet; Homeostasis; Human; Immune; Immune system; In Vitro; Inflammation; Inflammatory; Insulin Resistance; Interleukin-13; Interleukin-5; Interleukin-9; Intestines; Laboratories; Link; Lipids; Lymphoid Cell; Measures; Mediating; Metabolic; Metabolic Diseases; Methods; Mus; Non obese; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Obesity associated disease; Pathogenesis; Pathway interactions; Phenotype; Population; Population Group; Prevention strategy; Regulation; Research; Role; Smooth Muscle; Sorting - Cell Movement; Stress; Sympathetic Nervous System; System; TSLP gene; Testing; United States; Weight Gain; Work; base; blood glucose regulation; cell type; cost; cytokine; eosinophil; feeding; inhibitor/antagonist; insight; lipid metabolism; loss of function; macrophage; novel; public health relevance; receptor expression; response; selective expression; transcriptome

 DESCRIPTION (provided by applicant): Obesity, a metabolic disorder characterized by excess accumulation of adipose tissue, is associated with the development of numerous diseases such as Type 2 diabetes, cardiovascular disease, and colon cancer. Consequently, understanding the pathways involved in the development of obesity is critical to develop strategies for the prevention and treatment of this disease and co-morbidities. White adipose tissue (WAT) in humans and mice is populated by numerous immune cell types, including a recently identified population of group 2 innate lymphoid cells (ILC2s), which critically regulate WAT homeostasis by producing cytokines that modulate systemic metabolic homeostasis and energy expenditure. These findings suggest that immune cells can contribute to the development of obesity, though how the immune system regulates metabolic homeostasis remains poorly defined. Our preliminary studies show that ILC2 depletion is associated with increased weight gain and insulin resistance in mice fed a high-fat diet (HFD), suggesting that ILC2s may negatively regulate the development of obesity. However, pathways controlling ILC2 regulation and function in the context of pathogenic obesity remain unclear. Type 2 inflammation, mediated by ILC2s, is associated with suppression of the β2AR-dependent sympathetic nervous system, and this pathway has been targeted therapeutically to treat chronic diseases associated with ILC2 responses. Importantly, our preliminary data reveal that human and murine ILC2s express β2AR and that β2AR is a direct negative inhibitor of ILC2 responses in the intestine. We therefore hypothesize that the β2AR pathway negatively regulates WAT ILC2- mediated metabolic homeostasis, which induces weight gain in response to stress, thereby promoting the development of obesity. In the proposed research, we will investigate the role of the β2AR pathway in human and murine WAT ILC2 development, function, and regulation of metabolic homeostasis. In addition to providing new insights into the pathways controlling WAT ILC2 regulation and function, results from these studies will assess the potential of modulating the β2AR pathway using existing therapies to promote WAT ILC2-mediated metabolic homeostasis, and may enhance the development of more effective strategies to treat pathogenic obesity.

 描述（由申请人提供）：肥胖是一种以脂肪组织过度积累为特征的代谢性疾病，与多种疾病的发生有关，例如 2 型糖尿病、心血管疾病和结肠癌，研究人员了解了其发生的途径。肥胖的研究对于制定预防和治疗这种疾病和并发症的策略至关重要。人类和小鼠的白色脂肪组织 (WAT) 中含有多种免疫细胞类型，包括最近发现的第 2 组先天淋巴细胞群。 (ILC2)，它通过产生调节全身代谢稳态和能量消耗的细胞因子来严格调节 WAT 稳态。这些研究结果表明，免疫细胞可能导致肥胖的发生，尽管我们的初步研究仍不清楚免疫系统如何调节代谢稳态。研究表明，ILC2 的消耗与高脂饮食 (HFD) 喂养的小鼠体重增加和胰岛素抵抗有关，这表明 ILC2 可能对肥胖的发展产生负向调节作用，但控制 ILC2 调节的途径。由 ILC2 介导的 2 型炎症与 β2AR 依赖性交感神经系统的抑制有关，并且该通路已被用于治疗与 ILC2 反应相关的慢性疾病。我们的初步数据表明，人类和小鼠 ILC2 表达 β2AR，并且 β2AR 是肠道中 ILC2 反应的直接负性抑制剂，因此我们发现 β2AR 途径负向调节 WAT ILC2-。介导的代谢稳态，导致体重增加以应对压力，从而促进肥胖的发展。在拟议的研究中，我们将研究 β2AR 通路在人类和小鼠 WAT ILC2 发育、功能和代谢稳态调节中的作用。除了提供关于控制 WAT ILC2 调节和功能的途径的新见解外，这些研究的结果还将评估使用现有疗法调节 β2AR 途径以促进 WAT ILC2 介导的代谢稳态的潜力，以及可能会促进开发更有效的策略来治疗致病性肥胖。