Project Summary/Abstract: Research: Insulin resistance is a major cause for type 2 Diabetes (T2D) and is implicated in many life- threatening complications of T2D. A better understanding of the molecular mechanisms for insulin resistance is essential to develop potent and safe insulin sensitizers, which could reduce the social and economic burden of metabolic diseases. Our lab discovered a novel class of anti-inflammatory and anti-diabetic lipids, Palmitic Acid Hydroxy Stearic Acids (PAHSAs). PAHSA levels strongly correlate with insulin sensitivity in humans and are down-regulated in adipose tissue (AT) from insulin resistant subjects. PAHSAs are potent hepatic and systemic insulin sensitizers in obese T2D mice. This project will identify the mechanisms for the regulation of PAHSAs in altered metabolic states in vivo and the enzymes mediating their biosynthesis and degradation, providing novel strategies to prevent or treat T2D. Specific Aim1: To determine the mechanisms that regulate PAHSA levels in vivo. Specific Aim2: To identify candidate enzymes for PAHSA biosynthesis and degradation in our unique genetic mouse models of altered glucose homeostasis. Specific Aim3: To identify natural genetic drivers of PAHSA metabolism using the established profiling of the natural genetic variation among 8 mouse strains to mimick human variation. These studies will uncover novel pathways at the crossroad between AT lipogenesis and insulin sensitivity that can be manipulated to prevent or treat T2D. Candidate’s career development plan and career goals: I am highly committed to elucidate the mechanisms for insulin resistance and T2D with the ultimate goal of expanding the therapeutic armamentarium for T2D. During my postdoctoral training in Dr. Barbara’s Kahn lab, I became interested in the connections between AT lipogenesis and systemic insulin sensitivity. During the K01 award, I will acquire the necessary skills to study lipid metabolism in vivo combining innovative and powerful multiomic approaches and molecular biology. The studies in this K01 proposal will be conducted under the mentorship of Drs. Kahn and Saghatelian with the guidance of an outstanding scientific advisory committee (Drs. Alan Attie, Joshua Rabinowitz, and Evan Rosen), who are highly committed to my development into an independent scientist. Periodic meetings with these experts will center on experimental design, discussion of results, future directions, and preparation of R01 and R03 grants. My long-term career goal is to become an NIH-funded independent scientist. The training received during this K01 award is necessary for my successful transition to independent investigator in the Academia. Environment: The BIDMC Endocrine Division is the ideal site for training of young scientists towards a path of independence because it offers unparalleled opportunities for interactions with leaders in the fields of diabetes and metabolism. Graduates from this Division have made transformative di...