Role of miR-6236 in Obesity-Associated Adipose Tissue Dysfunction

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PROJECT SUMMARY/ABSTRACT This proposed two-year project stems directly from studies and career development activities related to my current K08 (DK116668), and represents a new research direction that will enhance my advancement towards independence through the generation of preliminary data and publications to support an R01-level application on how adipose tissue macrophages (ATMs) influence adipose tissue homeostasis and organismal metabolism. During the first two years of my K08 award I published multiple papers, obtained a tenure-track assistant professorship at the University of Pennsylvania (Penn), and initiated my independent research program at Children’s Hospital of Philadelphia (CHOP). With the continued mentorship of Dr. Mitchell Lazar and my K08 advisory committee, my independent research lab has grown dramatically in its first year and now numbers six full-time research staff, graduate students, and post-docs. I have obtained independent foundation support for my lab, and an NIH supplement to study the role of ATMs in HIV-associated metabolic dysfunction. We have published our first fully-independent (senior author) research manuscripts, and I have been invited to speak at multiple national conferences. My lab is now ready to accelerate our research program in ATMs in preparation for the transition to R01 funding. My R03 proposal focuses on understanding how a novel, ATM-secreted microRNA (miR-6236) influences adipocyte functions and organismal metabolism in the context of obesity. miR-6236 is both a novel miRNA, and the most highly expressed and highly secreted ATM miRNA. To facilitate our studies of this molecule, we have developed two novel transgenic mouse models that allow for whole organism or tissue-specific loss-of-function of miR-6236 in vivo. Whole body deletion of miR-6236 leads to increased weight gain, and impaired glucose control in the context of obesity. We have also developed in vitro models that preliminarily suggest that miR- 6236 controls mitochondrial respiration in adipocytes. Together, these data support our primary hypothesis that miR-6236 protects against obesity and it’s sequela by influencing how ATMs function in, and interact with, their tissue environment. We will test this hypothesis by crossing an established miR-6236 LoxP mouse line to the LysM-Cre most strain, effectively deleting miR-6236 in the myeloid immune lineages. The goal of this proposal is to comprehensively phenotype the effects of myeloid-specific miR-6236 deficiency on the adipose tissue macrophages, adipocytes, and mammalian metabolism. This work is a natural extension of my K08, and will act as a paradigm for future studies of ATM-secreted miRNAs in my lab. Importantly, this proposal will support the generation of publications and preliminary data for an R01-level application in this field.