2015 Grant Award - Yi Guo, Ph.D.

Genetic Discovery of Obesity Genes using Systemic RNAi in Drosophila melanogaster Fat Bodies

Yi Guo, Ph.D.
Department of Biochemistry and Molecular Biology, Mayo Clinic

Obesity pandemic has a dramatic impact on human health. Obesity increases the risk for many diseases, including hypertension, osteoarthritis, dyslipidemia, type 2 diabetes, coronary heart disease, and stroke. Obesity and associated chronic diseases are a huge burden for individual families and our society as a whole. At the cellular level, obesity is caused by excess neutral lipid storage specifically within lipid droplets in adipocytes and other cell types. Lipid droplet is an unique cellular organelle stores “neutral lipids” enclosed by a monolayer of phospholipids, provides energy, signaling lipid molecules and membrane precursors for almost all cell types. Previous in vitro functional genomic studies and proteomics studies identified a few hundred proteins associate with lipid droplets and regulate their function in Drosophila culture cells. We aim to systematically study the function of these newly identified genes in vivo in regulating whole-body fat storage. We down-regulated these genes in Drosophila fat tissue and assay the total triacylglyceride (TG) content changes. Upon screening 850 RNAi fly lines, we identify 248 lines reduce TG content to less than 80% of the wild-type controls and 189 lines increase TG content to more than 120% of the wild-type controls. These results validate Drosophila as an efficient and rapid model to investigate obesity gene function in vivo at the genome scale. For the proposed study, we are specifically focusing on two groups of genes critical for fat storage. We aim to: 1) Investigate the function of Atlastin/REEP ER-shaping molecules in lipid-droplet size regulation; 2) Investigate the function of novel transcription factors in fat tissue differentiation. This study combines the in vitro functional genomic study to detail analysis of in vivo characterization of novel genes in fat storage. This exciting project will provide new therapeutic targets to reverse the excess lipid storage in obesity tissues.
The proposed study aims to understand the function of novel genes in regulating fat storage. It is highly relevant for providing new therapeutic targets to battle obesity pandemic.