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

摘要/摘要 神经元和局部中枢神经系统驻留的免疫细胞参与复杂的相互作用，以调节大脑功能。在……里面 下丘脑内侧基底核(MBH)是能量平衡的重要组成部分，富含脂肪的饮食迅速诱导 异质性髓系细胞群的炎症激活和积聚，广义为 小胶质细胞。我们证明，在这种情况下激活的小胶质细胞足以刺激食物的摄入和身体 体重增加，但启动这种反应的代谢因素尚不清楚。这项提议的目标是 确定肠道微生物区系在调节MBH髓系细胞功能中的作用。其目标是确定 特定的髓系群体对肠道微生物区系信号的反应并确定它们如何转导这一信号 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小说 以髓系细胞为基础的治疗干预，以限制饮食诱导的肥胖及其代谢后果。至 为了达到我们的目标，我们将利用我们在MBH髓系细胞单细胞图谱方面的专业知识来确定特定的 肠道微生物调控下的种群。饮食是影响肠道微生物区系组成的主要因素， 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变化 肠道中的微生物。这些变化可能影响MBH髓系细胞的功能。我们的目标是确定 肠道微生物区系在确定下丘脑对膳食饱和脂肪的髓系反应中的作用。这个 提出了以下次级目标：(1)确定膳食脂肪组成和肠道之间的相互作用 微生物区系影响下丘脑髓系反应；(2)确定肠道微生物区系的具体贡献 关于下丘脑的髓系功能。完成这项拟议的工作将为人们提供关于饮食如何 脂肪消耗和肠道微生物区系相互作用，调节饮食反应性MBH的功能多样性 髓系细胞和下丘脑对能量代谢的控制。

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.