Date of Graduation

5-2015

Document Type

Dissertation

Degree Name

Doctor of Philosophy in Biology (PhD)

Degree Level

Graduate

Department

Biological Sciences

Advisor/Mentor

Michael H. Lehmann

Committee Member

Yuchun Du

Second Committee Member

David S. McNabb

Third Committee Member

Gisela F. Erf

Keywords

Pure sciences, Biological sciences, Insulin signaling, Lipid metabolism, Tor signaling

Abstract

Lipins are a family of highly conserved proteins found from yeasts to humans. Lipins have dual functions, serving as phosphatidate phosphatase enzymes (PAP) in the synthesis of neutral fats (triacylglycerols, TAG) and as transcriptional co-regulators that affect the expression of genes involved in lipid and fatty acid metabolism. Thus, they play central roles in metabolic control. Disruption of Lipin function has been implicated in lipodystrophy, obesity and insulin resistance. Using dLipin, the Drosophila homolog of Lipin, as a model, I aimed to elucidate the relationship between the two biochemical functions of Lipin and metabolic homeostasis. I discovered there is a strong interconnection between TAG synthesis and insulin pathway activity. Reduced activity of dLipin and other enzymes involved in TAG synthesis disrupted insulin pathway activity by interfereing with phosphatidylinositol (3,4,5)-trisphosphate (PIP3) synthesis. Mosaic analysis revealed that cell-autonomous loss of dLipin activity in fat the body negatively affects cell growth. Genetic interaction experiments indicated that dLipin and the insulin pathway regulate adipogenesis in an interdependent fashion. Furthermore, I found that the nutrient sensing complex TORC1 regulates dLipin activity in lipid metabolism by controlling dLipin's subcellular localization. Hence, the insulin pathway as well as the TORC1 pathway each appears to be a central regulator of dLipin activity and its functions in lipid metabolism. Nuclear functions of dLipin did not seem to have an effect on insulin pathway activity. Thus, metabolic disturbances observed after dLipin knockdown seem to be primarily caused by reduced PAP activity provided by dLipin. Taken together, the results position dLipin as a central target to further study the link between TAG synthesis and insulin and TORC1 pathway activity.

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