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Why Make Fat?: The Impact of de novo Fatty Acid Synthesis on Fat Storage, Reproduction,and Longevity in C. elegans

Olsen, Carissa P. (2011) Why Make Fat?: The Impact of de novo Fatty Acid Synthesis on Fat Storage, Reproduction,and Longevity in C. elegans. PhD thesis, Fred Hutchinson Cancer Research Center / University of Washington .

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Abstract

Metabolic flux analysis allows for the understanding of how multiple pathways are integrated onto the core metabolism of an animal as it encounters different environmental and physiological challenges. Here, we have developed and implemented a stable 13C isotope approach in C. e/egans that allows us to monitor how the animals are utilizing their diet. This "mixed isotope" strategy can specifically quantify various aspects of fatty acid metabolism and can accurately determine whether the fats of the animals are absorbed directly from the diet or synthesized de novo. We have used this mixed labeling strategy to define how known fat storage genes, such as the insulin receptor, impact lipid metabolism pathways. In doing so, we have been able to establish that elevated de novo fatty acid synthesis is the main driver of fat accumulation in daf-2 animals. Additionally, this type of analysis allowed us to determine that the longevity and fat storage phenotypes of the daf-2 animals are separable. In addition, we have used this strategy to identify several novel regulators of de novo fatty acid synthesis. These regulators include oxidative phosphorylation and peroxisomal ~oxidation, which have not been previously implicated in the regulation of lipogenesis. In addition, we found that reproduction is also a key driver of de novo fatty acid synthesis as adult animals have significantly more synthesized fatty acids than their larval counterparts. Because reproduction requires a large amount of resources, we hypothesize that a lipogenic shift is an important component for successful progeny production and continued somatic maintenance. Finally, we have also found that RNAi of the fatty acid synthase gene results in a reduction in the adult lifespan indicating an important function for lipogenesis in the adult.

Item Type: Thesis (PhD)
Subjects: Cellular and Organismal Processes > Metabolism
Organisms > Model organisms
Depositing User: Craig Johansen
Date Deposited: 30 Sep 2011 22:55
Last Modified: 14 Feb 2012 14:44
URI: http://authors.fhcrc.org/id/eprint/499

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