Title: Metabolomics study of Ketosis-Associated Increases in FGF21 in Wild-type and PPAR alpha Knockout Mice.
Biography: Vladimir Tolstikov
Fibroblast growth factor 21 (FGF21) is a novel endocrine hormone that has a range of beneficial metabolic effects and consequently a number of exogenously administered FGF21-based therapeutics are under investigation. A potential alternative therapeutic strategy would be to increase endogenous production of FGF21, however an improved understanding of the metabolic factors involved in the regulation of FGF21 production is required. The ketotic state is one of the best described physiologic stressors associated with elevated FGF21 production and this regulation occurs, at least in part, via PPAR alpha. Eli Lilly and Company’s metabolomics platform, comprised of state-of-the-art instrumentation technologies, is capable of information delivery on hundreds of small molecules showing statistically significant biochemical alterations. Therefore, we applied a global metabolomics approach to examine the metabolic changes associated with FGF21 production in the livers of wild-type and PPAR alpha knockout mice in response to fasting or a ketogenic diet. Plasma FGF21 concentrations were increased by fasting and ketogenic diet in wild-type mice, but only by ketogenic diet in PPAR alpha KO mice and all increases correlated with increased FGF21 expression specifically in liver. Correlation analysis of metabolomics data detected a strong link between hepatic FGF21 expression and the glutathione-mercapturic acid pathway. Curve clustering analysis identified 2−dehydro−D−gluconate, deoxyribose−phosphate, and glycerol−3−phosphate\\\\\\\\r\\\\\\\\nas metabolites associated with FGF21 production independent of the regulation of PPAR alpha. The current metabolomics approach provides a novel means for furthering our understanding of the physiologic regulation of FGF21 production. \\\\\\\\r\\\\\\\\n
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