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

总结/摘要 神经元和局部CNS驻留免疫细胞参与复杂的相互作用以调节大脑功能。在 中基底下丘脑（MBH）是能量平衡的关键整合者，富含脂肪的饮食迅速诱导 骨髓细胞的异质群体的炎性激活和积聚，广义上称为 小胶质细胞我们发现，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，但引发这种反应的代谢因素尚不清楚。本提案的目的是 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来源的信号作出反应，并确定它们如何表达这种信号。 反应影响下丘脑调节代谢功能。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，以限制饮食诱导的肥胖及其代谢后果。到 为了达到我们的目标，我们将利用我们在MBH骨髓细胞单细胞谱方面的专业知识， 在肠道微生物调节下的种群。饮食是影响肠道微生物群组成的主要因素， 和富含饱和脂肪的饮食诱导不利的改变，在类型和数量的脂肪， 肠道中的微生物。这些变化可能影响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对膳食饱和脂肪的髓样反应中的作用。的 提出以下子目标：（1）确定膳食脂肪组成与肠道的相互作用 微生物群影响下丘脑髓样反应;（2）确定肠道微生物群的具体贡献 对下丘脑髓系功能的影响完成拟议的工作将提供新的见解如何饮食 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 骨髓细胞和下丘脑控制能量代谢。

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.