Adipose tissue macrophage polarization and its influence on adipocyte function

描述(由申请人提供)： 越来越多的证据表明，炎症可能是许多肥胖相关疾病发展的核心机制，包括代谢综合征和糖尿病。肥胖症的炎症性改变包括脂肪组织与炎性巨噬细胞的渗透。脂肪组织巨噬细胞(ATM)可以干扰正常脂肪细胞的功能，是肥胖小鼠产生全身性胰岛素抵抗的必要条件和充分条件。这项建议试图了解ATM改变脂肪细胞功能和促进胰岛素抵抗的机制。候选人的目标是(1)提高他在免疫学方面的熟练程度，(2)熟练地评估肥胖动物模型中的新陈代谢，以及(3)通过实现前两个目标，成为一名独立的研究人员，在肥胖引发炎症的机制以及肥胖如何影响人类疾病方面拥有专业知识。职业发展计划包括肥胖和新陈代谢专家的跨学科指导，趋化因子生物学专家的共同指导，以及与炎症和糖尿病专家的合作。初步研究表明，肥胖诱导ATM激活状态从瘦小鼠的抗炎交替(M2)激活状态转变为肥胖小鼠的促炎(M1)激活状态。虽然M1巨噬细胞使脂肪细胞产生胰岛素抵抗，但M2巨噬细胞产生的IL-10保护脂肪细胞免受TNFpha的负面影响。实验将验证IL-10可以防止肥胖引起的脂肪组织炎症变化的假设。该研究计划将(1)评估IL-10促进正常脂肪细胞功能的机制，(2)评估IL-10对肥胖小鼠ATM积聚和激活的抑制作用，以及(3)检验IL-10在巨噬细胞中过表达将防止肥胖小鼠脂肪组织炎症和改善胰岛素敏感性的假设。在资助期结束时，候选人预计将根据他的发现申请独立资金，以进一步剖析肥胖导致的人类和老鼠的炎症性变化。相关性：这项建议检验了肥胖小鼠的胰岛素抵抗可以通过阻断脂肪组织中巨噬细胞的炎症激活来预防的假设。这将促进我们对肥胖、炎症和人类2型糖尿病之间关系的理解。

DESCRIPTION (provided by applicant): Growing evidence suggests that inflammation may be a central mechanism behind the development of many obesity-related diseases that include the metabolic syndrome and diabetes. Inflammatory changes in obesity include the infiltration of fat tissue with inflammatory macrophages. Adipose tissue macrophages (ATMs) can perturb normal adipocyte function and are necessary and sufficient to generate systemic insulin resistance in mouse models of obesity. This proposal seeks to understand the mechanisms by which ATMs alter adipocyte function and contribute to insulin resistance. The candidate's goals are (1) to increase his proficiency in immunology, (2) to become adept at the assessment of metabolism in animal models of obesity, and (3) through achieving the first two goals, to become an independent investigator with expertise in the mechanisms by which obesity generates inflammation and how this impacts human disease. The career development plan includes interdisciplinary mentorship from an expert in the obesity and metabolism, co-mentorship from an expert in chemokine biology, and collaboration with specialists in inflammation and diabetes. Preliminary studies indicated that obesity induced a switch in ATM activation state from an anti- inflammatory alternatively (M2) activated state in lean mice to a pro-inflammatory (M1) activated state in obese mice. While M1 macrophages rendered adipocytes insulin resistant, IL-10 produced from M2 macrophages protected adipocytes from the negative effects of TNFalpha. Experiments will test the hypothesis that IL-10 can prevent inflammatory changes in adipose tissue induced by obesity. The research plan will (1) assess the mechanisms by which IL-10 promotes normal adipocyte function, (2) assess the suppressive effects of IL-10 on ATM accumulation and activation in obese mice, and (3) test the hypothesis that IL-10 overexpression in macrophages will prevent adipose tissue inflammation and improve insulin sensitivity in obese mice. At the end of the funding period, the candidate expects to apply for independent funding based on his findings to further dissect the inflammatory changes caused by obesity in humans and mice. Relevance: This proposal examines the hypothesis that insulin resistance in obese mice can be prevented by blocking the inflammatory activation of macrophages in fat tissue. This will advance our understanding of the relationship between obesity, inflammation, and Type 2 Diabetes in humans.