Adipose Tissue Macrophage Control of Metabolic Dysfunction in Diabetes

项目总结 肥胖引起的炎症是肥胖和糖尿病之间的一种公认的机制联系。脂肪 组织巨噬细胞(ATM)位于脂肪组织免疫网络的中心。许多知识鸿沟 存在关于ATM生物学及其与人类代谢性疾病的关系。ATM的工作原理 它们的激活状态如何与2型糖尿病(DM)相关，以及它们是如何沟通的 用前脂肪细胞和脂肪细胞来调节营养储存还不完全清楚。这样做的目的是 一项建议是通过对人类脂肪组织样本的补充研究来解决这些知识差距 和老鼠模型。这个项目中假设的科学前提植根于对 肥胖(DM)受试者内脏脂肪组织CD206+ATM较高，较少 与肥胖的非糖尿病患者相比，前脂肪细胞、较大的脂肪细胞和表现为脂肪细胞代谢功能障碍 研究对象。我们提出了一个通过原位增殖阻断扩增CD206+ATM的模型 前体脂肪细胞的增殖和分化，以产生功能失调的脂肪组织环境。我们会 评估CSF1可能是人类CD206+ATM的激活剂，并评估CCL18作为一种 CD206+ATM分泌趋化因子，介导ATM-前体脂肪细胞之间的通讯。如果完成我们的提案 将极大地促进我们对人类代谢性炎症是如何独立于 肥胖并导致当前ATM功能模型的大幅修订。 为了评估我们的模型，我们建议完成三个具体目标：1)定义CD206+的机制 HATM增殖及其与脂肪细胞肥大和糖尿病状态的关系2)确定机制 潜在的CD206+ATM-前体脂肪细胞串扰以及由此产生的前体脂肪细胞和脂肪细胞代谢 功能障碍。3)评价ATM来源的CCL18在脂肪组织炎症调节中的作用 和新陈代谢。用于所有目标的实验方法利用来自大型减肥手术的组织样本 年龄和性别不同的队列，以及炎症和代谢功能的分析。这项研究将 使用外科医生和基础科学家之间的团队科学方法来实现其目标，以缩小差距 在人类和小鼠模型中，我们对间火的理解之间存在差异。如果完成，我们的研究就可以 通过确定独立于肥胖的糖尿病风险的新生物标记物和糖尿病的新途径来影响健康 治疗性干预。

PROJECT SUMMARY Obesity-induced inflammation is a well-established mechanistic link between obesity and diabetes. Adipose tissue macrophages (ATMs) lie at the center of the adipose tissue immune network. Many knowledge gaps exist regarding ATM biology and its relationship to human metabolic disease. The mechanisms of ATM accumulation, how their activation state relates to type 2 diabetes mellitus (DM), and how they communicate with preadipocytes and adipocytes to regulate nutrient storage are incompletely understood. The goal of this proposal is to address these knowledge gaps using complementary studies in human adipose tissue samples and mouse models. The scientific premise for the hypotheses in this project is rooted in the observation from our groups that visceral adipose tissue from obese (DM) subjects have higher CD206+ ATMs, fewer preadipocytes, larger adipocytes, and manifest adipocyte metabolic dysfunction compared to obese non-DM subjects. We propose a model whereby the expansion of CD206+ ATMs by in situ proliferation blocks preadipocyte proliferation and differentiation to generate a dysfunctional adipose tissue environment. We will evaluate CSF1 as a putative activator of CD206+ ATMs in humans and evaluate the function of CCL18 as a CD206+ ATM secreted chemokine that mediates ATM-preadipocyte communication. If completed our proposal will significantly advance our understanding of how human metabolic inflammation develops independent of obesity and lead to substantial revisions in the current models of ATM function. To evaluate our model, we propose to complete three specific aims: 1) To define mechanisms of CD206+ hATM proliferation and its relationship to adipocyte hypertrophy and DM status. 2) To identify mechanisms underlying CD206+ ATM-preadipocyte crosstalk and resultant preadipocyte and adipocyte metabolic dysfunction. 3) To evaluate the role of ATM-derived CCL18 in the regulation of adipose tissue inflammation and metabolism. The experimental approach for all aims utilize tissue samples from a large bariatric surgery cohort with diversity in age and sex, and assays of inflammatory and metabolic function. This study will accomplish its goals using a team science approach between surgeons and basic scientists to close the gap between our understanding of metainflammation in human and murine models. If completed our study can impact health by identifying new biomarkers for DM risk independent of obesity and new pathways for therapeutic interventions.