Adipose-Specific Phosphatidic Acid Phosphatase Activity of Lipin 1 Regulates Systemic Insulin Sensitivity

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ABSTRACT In this K01 Mentored Scientist Development Award application, Dr. Andrew J. Lutkewitte outlines a detailed strategy to further enhance his research training using sophisticated metabolic and lipidomic analysis. He will utilize these approaches to discover novel mediators of systemic insulin resistance driven by insufficient adipose tissue lipogenic capacity in obesity. Dr. Lutkewitte is currently a postdoctoral research fellow at Washington University School of Medicine’s Division of Geriatrics and Nutritional Sciences. He has a strong background in whole-body physiology and metabolism that he will draw upon to investigate adipose function during metabolic stress. A primary goal of Dr. Lutkewitte is to become and independent investigator in lipid metabolism and obesity-induced insulin resistance. He has carefully developed a research strategy with an integrated career development and mentoring plan to ensue realization of this goal. Each of the chosen mentors are leading experts in their respective fields which are directly related to this proposal. The primary mentor Dr. Brian Finck will assist with the metabolic characterization and analysis of both animal and cell culture models. From Dr. Nada Abumrad, he will learn stromal vascular fraction isolations, gain understanding about mechanisms of adipocyte differentiation and lipogenesis, and fundamentals of lipid uptake/export. Dr. Gary Patti will train Dr. Lutkewitte in both targeted and untargeted metabolomics as well as metabolic flux analysis using isotopic tracers in vivo. Besides research training, Dr. Finck and a “Near Peer” mentoring team will provide Dr. Lutkewitte with the essential skills to initiate and maintain a successful, independent laboratory. The ability of adipose tissue to regulate lipid stores (mainly, triglycerides) is vital for preserving metabolic health. In fact, an imbalance between the appropriate release (lipolysis) or synthesis (lipogenesis) of lipids in adipose tissue increases the risk of pathologies such as non-alcoholic fatty liver disease, systemic insulin resistance and ultimately type 2 diabetes. Yet, the fundamental mechanisms of how adipose tissue regulates systemic insulin sensitivity remain unclear. Recent evidence suggests that phosphatidic acid, the substrate for lipin 1, a phosphatidic acid phosphatase, is present at high levels in the blood and has deleterious effects in insulin sensitive tissues such as skeletal muscle and liver. The goals of this work are to: [1] determine how the posttranslational modification, acetylation, effects lipin 1 activity and cellular localization, [2] discover the specific acetylated lysine residues regulating lipin 1, [3] define how adipose tissue lipin 1 regulates whole-body metabolism and insulin sensitivity, and [4] to identify how phosphatidic acid and similar lipids mediate these effects. The end goal of this research progression is to develop Dr. Lutkewitte into a productive, independent investigator. Together the training in research and career development plan outlined here will provide him with the knowledge and expertise to secure an independent academic position and R01-type funding.