Molecular Genetics of Lipid Metabolism

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DESCRIPTION (provided by applicant): Obesity has emerged as a world-wide health problem over the past several decades. Its complications are costly on individual and societal levels. There is urgent need to identify new drug targets for ameliorating the metabolic consequences of obesity such as type 2 diabetes mellitus, hyperlipidemia, and non-alcoholic fatty liver disease. One central aspect of obesity and its attendant illnesses that requires greater understanding is how the organism can safely store the excess lipids that accumulate throughout the body in this condition. Work over the past decade has revealed that the adipose tissue is a "battery of finite capacity," and that spill-over of lipid surplus into other tissues and organs contributes to diseas burden. This application seeks to address the need for new drug targets to combat obesity and its related illnesses by responding to the NIH's "Genetic Screens to Enhance Zebrafish Research (R01)" Funding Opportunity. A proposal to perform a large-scale forward genetic screen in zebrafish for lipid metabolic phenotypes, with a focus on hepatic steatosis (excess lipids in the liver) and altered adipose mass, is presented. We provide preliminary data underscoring both the feasibility of studying lipid metabolism in this model organism, and for identifying and characterizing completely novel and potentially druggable nodes of energy metabolism. We demonstrate that a wide-range of methods including molecular genetic, whole-animal physiologic, nutritional, biochemical, electrophysiologic, and microscopic techniques can be successfully applied to the study of mutants we intend to isolate in this screen in the hopes of arriving at a comprehensive view of how mutation of a single gene can give rise to complex metabolic phenotypes.