Adipose Tissue Macrophage Control of Metabolic Dysfunction in Diabetes

脂肪组织巨噬细胞对糖尿病代谢功能障碍的控制

• 批准号: 9400748
• 负责人: Carey N Lumeng
• 金额: $ 58.11万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-07-18 至 2021-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9400748
• 关键词: Address; Adipocytes; Adipose tissue; Age; Apoptosis; Bariatrics; Biological Assay; Biological Markers; Biology; CCL18 gene; CSF1 gene; Cells; Cellular biology; Clinical; Clinical Research; Coculture Techniques; Collaborations; Collagen; Communication; Data; Diabetes Mellitus; Environment; Functional disorder; Genes; Genetic Transcription; Glucocorticoids; Goals; Health; Human; Hyperplasia; Hypertrophy; IL4 gene; Immune; In Situ; Inflammation; Inflammatory; Inflammatory Response; Insulin Resistance; Interleukin-4; Knowledge; Lead; Link; Measures; Mediating; Mediator of activation protein; Metabolic; Metabolic Control; Metabolic Diseases; Metabolism; Modeling; Mus; Non obese; Non-Insulin-Dependent Diabetes Mellitus; Nutrient; Obese Mice; Obesity; Pathogenesis; Pathway interactions; Patients; Phenotype; Physicians; Physiological; Plant Roots; Population; Process; Proliferating; Regulation; Research; Risk; Risk Factors; Rodent Model; Role; Science; Scientist; Stimulus; Stromal Cells; Supporting Cell; Surgeon; System; Therapeutic Intervention; Thinness; Tissue Sample; Visceral; Xenograft Model; adipocyte biology; age related; bariatric surgery; base; chemokine; cohort; diabetes risk; diabetic; disorder risk; functional gain; gain of function; in vivo; innovation; interest; lipid biosynthesis; macrophage; mouse model; non-diabetic; novel; novel marker; patient population; patient stratification; pre-clinical; predictive marker; receptor; response; sex; targeted treatment; three-dimensional modeling; tissue biomarkers

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.

项目摘要 肥胖引起的炎症是肥胖与糖尿病之间建立的机械联系。脂肪 组织巨噬细胞（ATM）位于脂肪组织免疫网络的中心。许多知识差距 存在于ATM生物学及其与人类代谢疾病的关系。 ATM的机制 积累，其激活状态与2型糖尿病（DM）的关系以及它们如何交流 尚不完整地使用前脂肪细胞和脂肪细胞来调节养分的储存。目标的目标 建议是通过人类脂肪组织样本中的互补研究来解决这些知识差距 和鼠标模型。该项目中假设的科学前提源于 我们的肥胖受试者内脏脂肪组织（DM）的组具有较高的CD206+ ATM，更少 与肥胖的非DM相比 主题。我们提出了一个模型，该模型通过原位增殖块扩展CD206+ ATM 前脂肪细胞增殖和分化以产生功能失调的脂肪组织环境。我们将 评估CSF1作为人类CD206+ ATM的推定激活剂，并评估CCL18的功能 CD206+ ATM分泌的趋化因子介导ATM-Preadipocyte通信。如果完成了我们的建议 将大大提高我们对人类代谢炎症如何独立发展的理解 肥胖并导致当前ATM功能模型的重大修订。 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扩散及其与脂肪细胞肥大和DM状态的关系。 2）确定机制 基础CD206+ ATM-尖头细胞串扰和由此产生的前脂肪细胞和脂肪细胞代谢 功能障碍。 3）评估ATM来源的CCL18在调节脂肪组织炎症中的作用 和新陈代谢。所有目标的实验方法都利用大型减肥手术的组织样品 队列与年龄和性别的多样性，以及炎症和代谢功能的测定。这项研究会 使用外科医生和基本科学家之间的团队科学方法来实现其目标，以缩小差距 在我们对人和鼠模型中元炎症的理解之间。如果完成的话，我们的学习可以 通过确定独立于肥胖的新生物标志物和新的生物标志物来影响健康 治疗干预措施。