dLipin interacts with the insulin signaling pathway in the control of fat metabolism and growth. Michael Lehmann, Sandra Schmitt. Dept Biological Sci, Univ Arkansas, Fayetteville, AR.

   Lipins are central regulators of adipose tissue development and fat storage in both fruit flies and mammals. Loss of the single lipin homolog in Drosophila, dLipin, and the mammalian lipin 1 paralog both lead to severe underdevelopment of the fat tissue and diminished organismal stores of neutral fats (triacylglycerides, TAG). This phenotype was in part explained by the discovery that lipins are phosphatidate phosphatases that catalyze the penultimate step of the glycerol-3-phosphate pathway leading to TAG. However, lipins can also translocate into the cell nucleus where they participate in gene regulation as transcriptional co-regulators. Nuclear translocation of lipin 1 is controlled by TOR-dependent phosphorylation of the protein in response to insulin signaling. We found that, in Drosophila, dLipin shows a strong genetic interaction with the insulin pathway and TOR, resulting in enhanced fat body defects and reduced viability. Lack of TOR induces migration of dLipin into the nucleus indicating that under fasting conditions dLipin has primarily gene regulatory functions. Intriguingly, in genetic mosaic animals, fat body cells lacking dLipin were not only deficient in fat droplets, but also showed a cell-autonomous growth defect. This induced us to more closely examine insulin signaling in fat body cells containing reduced levels of dLipin. We found a strong reduction of PIP3 in these cells, the second messenger that mediates insulin/PI3K signaling. At the same time, levels of PIP2, the substrate of PI3K and direct precursor of PIP3, were unchanged. In addition, we found that animals lacking dLipin have substantially elevated sugar levels in their hemolymph. Together, these data indicate that lack of dLipin causes insulin resistance and suggest a novel function of the protein, which is to provide feed back regulation of the insulin signaling pathway. Elucidation of the mechanism by which dLipin controls the insulin response will help us understand how organisms coordinate cell growth and the creation of energy stores.