Summary/Abstract Recent work, including that from our group, has highlighted a role for microglia, innate immune cells of the CNS, in mediating diet-induced dysfunction in the hypothalamus, a brain region controlling energy intake and expenditure. The objective of this proposal is to identify specific microglial populations responsive to diet- associated signals, and determine how they transduce this response to influence hypothalamic control over metabolic function. The goal is to use this information to target microglia in order to produce new, powerful, and specific ways to limit diet-induced obesity and its metabolic consequences. To reach our objective, we have developed innovative mouse models to identify subsets of microglia in confined areas such as the mediobasal hypothalamus, and to specifically measure the genome-wide transcriptional impact of dietary excess on hypothalamic microglia, infiltrating macrophages, and neurons critical to metabolic control. We will combine these tools with others allowing us to manipulate the number and polarization of microglia, in order to determine how microglia modulate the function of neuronal circuits controlling energy balance. The following aims are proposed: (1) Identify the diversity of hypothalamic microglia that are responsive to signals linked to dietary excess; (2) Determine the molecular mechanisms by which A20, a key regulator of inflammatory function, restricts the diet-induced inflammatory activation of hypothalamic microglia; and (3) Determine the mechanisms by which hypothalamic microglia modulate neuronal gene expression. Completing the proposed work holds promise to reveal new and unexpected strategies to mitigate obesity and its consequences. The Candidate, Dr. Martin Valdearcos, is training in the lab of Dr. Suneil Koliwad at the University of California San Francisco (UCSF). Dr. Valdearcos' work on microglia has led him to create a research niche focused on immunologic determinants of hypothalamic function that is distinct from that of Dr. Koliwad. The career development goal of this proposal, therefore, is to optimally foster Dr. Valdearcos' emerging research program and forge a path towards academic independence. To achieve this, he will in addition to receiving career-focused mentorship from Dr. Koliwad, also receive intensive mentorship from Dr. Allison Xu, a leader in hypothalamic physiology and Dr. Katerina Akassoglou, an expert in neuroinflammation and microglial function. Dr. Valdearcos' career development plan also involves formal courses in immunology, hypothalamic physiology and genomic technologies. Finally, he has a strategically designed advisory committee that includes Drs. Ajay Chawla, Averil Ma, Zachary Knight and Mark Ansel, who each bring a wealth of content- specific expertise designed to guide Dr. Valdearcos' in gaining exactly the expertise he will need going forward.