The role of gut microbiota in regulating functional diversity of diet-responsive hypothalamic myeloid cells

肠道微生物群在调节饮食反应性下丘脑骨髓细胞功能多样性中的作用

基本信息

批准号：
10219248
负责人：
Martin Valdearcos
金额：
$ 12.11万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-08-01 至 2023-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10219248
关键词：
Affect Blood Vessels Body Weight Brain Brain region Cell Therapy Cell physiology Cells Complex Consumption Data Data Set Detection Diet Dietary Fats Eating Energy Metabolism Exhibits Fatty acid glycerol esters Functional disorder Gene Expression Germ-Free Goals Hand Heterogeneity Homeostasis Hyperphagia Hypothalamic structure ITGAM gene Immune Immune system Individual Inflammation Inflammatory Knowledge Lead Mammals Mediator of activation protein Metabolic Metabolic Diseases Metabolism Microglia Molecular Molecular Profiling Morphology Mus Myelogenous Myeloid Cells Neurons Obesity Obesity Epidemic Pathogenesis Pathway interactions Peripheral Phenotype Population Population Heterogeneity Property Reducing diet Regulation Research Research Proposals Role Shapes Signal Transduction Testing Therapeutic Intervention Up-Regulation Weight Gain Work cell type design diet-induced obesity dietary dietary constituent energy balance fatty acid metabolism germ free condition gut microbes gut microbiota immune function improved innovation insight lipid transport microbial microbiota microorganism novel public health relevance response saturated fat transcriptomics western diet

项目摘要

Summary/Abstract Neurons and local CNS-resident immune cells engage in complex interactions to regulate brain function. In the mediobasal hypothalamus (MBH), a critical integrator of energy balance, diets rich in fat rapidly induce the inflammatory activation and accumulation of a heterogeneous population of myeloid cells, broadly termed microglia. We showed that microglia activated in this context are sufficient to stimulate food intake and body weight gain, however the metabolic factors initiating this response are unknown. The goal of this proposal is to determine the role of the gut microbiota in regulating the function of MBH myeloid cells. The objective is to identify specific myeloid populations responsive to gut microbiota-derived signals and determine how they transduce this response to influence hypothalamic regulation of metabolic function. We will use this information to design novel myeloid cell-based therapeutic interventions to limit diet-induced obesity and its metabolic consequences. To reach our objective, we will leverage our expertise in single-cell profiling of MBH myeloid cells to define specific populations under gut microbial regulation. Diet is a major factor affecting the composition of the gut microbiota, and diets rich in saturated fat induce unfavorable alterations in the type and numbers of commensal microorganisms in the gut. These changes may impact MBH myeloid cell function. Our aim is to determine the contribution of the gut microbiota in determining hypothalamic myeloid responses to dietary saturated fat. The following sub-aims are proposed: (1) Determine how the interaction between dietary fat composition and gut microbiota influences hypothalamic myeloid responses; (2) Determine the specific contribution of gut microbiota on hypothalamic myeloid function. Completing the proposed work will provide novel insights into how the dietary fat consumption and the gut microbiota interact to regulate the functional diversity of diet-responsive MBH myeloid cells and the hypothalamic control of energy metabolism.

摘要/摘要神经元和局部中枢神经系统驻留免疫细胞参与复杂的相互作用来调节大脑功能。在下丘脑中基底层（MBH）是能量平衡的关键整合者，富含脂肪的饮食会迅速诱导异质性骨髓细胞群的炎症激活和积累，广义上称为小胶质细胞。我们表明，在这种情况下激活的小胶质细胞足以刺激食物摄入和身体体重增加，但是引发这种反应的代谢因素尚不清楚。该提案的目标是确定肠道微生物群在调节 MBH 骨髓细胞功能中的作用。目标是确定特定的骨髓细胞群对肠道微生物群衍生的信号做出反应，并确定它们如何转导这种信号影响下丘脑代谢功能调节的反应。我们将利用这些信息来设计新颖的基于骨髓细胞的治疗干预措施，以限制饮食引起的肥胖及其代谢后果。到为了实现我们的目标，我们将利用我们在 MBH 骨髓细胞单细胞分析方面的专业知识来定义特定的受肠道微生物调节的人群。饮食是影响肠道菌群组成的主要因素，富含饱和脂肪的饮食会导致共生体的类型和数量发生不利的改变肠道内的微生物。这些变化可能会影响 MBH 骨髓细胞功能。我们的目标是确定肠道微生物群在确定下丘脑骨髓对膳食饱和脂肪反应中的贡献。这提出以下子目标：（1）确定膳食脂肪成分与肠道之间的相互作用微生物群影响下丘脑髓系反应； (2)确定肠道菌群的具体贡献对下丘脑髓样功能的影响。完成拟议的工作将为饮食如何提供新的见解脂肪消耗和肠道微生物群相互作用调节饮食反应性 MBH 的功能多样性骨髓细胞和下丘脑对能量代谢的控制。