Research

	Regulation of feeding behavior and fat storage
	Obesity is the leading cause of type-2 diabetes, cardiovascular diseases and hypertension, the so-called Metabolic Syndrome. We are broadly interested in how body fat level is maintained in animals and how it can be disrupted through genetic and dietary perturbations. Our laboratory primarily uses the nematode C. elegans as a model organism to elucidate the genetic pathways and molecular mechanisms that regulate food intake, fat storage and mobilization. Most of our studies begin with large-scale forward genetic screens in C. elegans. We then employ genetics, lipid and protein biochemistry, high-throughput sequencing technology, fluorescence and electron microscopy to address our questions at a molecular level.
			Feeding behavior Body fat is derived from the diet and de novo synthesis. Therefore, changes in feeding behavior may have a direct impact on fat intake. Our studies on feeding behavior were motivated by the identification of a genetic mutant that expressed a constitutively active cGMP dependent protein kinase (PKG). This mutant showed a profound lack of foraging behavior. Through genetic and biochemical analysis, we identified a novel transcriptional co-repressor complex that mediated the kinase activity. In the future, we will address the following questions: (1) What is the signal transduction pathway that links PKG activity to the transcriptional machinery; (2) What are the target genes that respond to PKG activation?
			Fat storage and mobilization The lipid droplet is the subcellular organelle where neutral lipids are stored. In metazoans, lipid droplets vary in number and size in different tissues, and they undergo dynamic changes that reflect the metabolic status and dietary intake of the organism as a whole. Another of our long-term goals is to identify the genetic pathways that govern lipid droplet size and number. We have isolated many mutants that accumulated grossly enlarged lipid droplets. Molecular cloning of these mutants revealed a role for peroxisomal fatty acid beta-oxidation in the regulation of lipid droplet size. In the future, we will address the following questions: (1) What are the dietary factors that modulate lipid droplet size; (2) What are the molecular mechanisms that govern lipid droplet fission and fusion?
			Transgene silencing and RNAi In studying the regulation of a triglyceride lipase, we have fortuitously generated a transgene that undergoes periodic silencing. Using this highly sensitive reporter, we have discovered a number of novel genes required for transgene silencing and RNA interference (RNAi). We currently are using an interdisciplinary approach to determine the molecular function of these new RNAi pathway components.