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.