Genetic and genomic investigations of fat storage and metabolism in C. elegans. Obesity afflicts millions of world citizens. The health problems associated with obesity are rising at epidemic rates, challenging world health care systems to provide adequate care. The long-term goal of this research is to dissect the pathways of fat regulation to better understand the mechanisms by which specific genes act to either promote or facilitate resistance to obesity. Our work in the model organism Caenorhabditis elegans has led the identification of conserved regulators of lipid homeostasis. The central hypothesis underlying these studies is that changes in fat stores occur as a result of interactions between regulatory pathways and downstream lipid metabolism genes. This grant proposes to identify fat-regulatory and fat-modulating genes downstream of the key transcriptional regulators NHR-64 and DAF-16/FoxO. The identification of lipid regulators, their functional roles, and their place in the genetic regulatory hierarchy will be explored by means of gene expression studies, genetic epistasis analysis, functional studies using RNA interference, and lipid analysis. An extensive collection of mutants, together with the powerful genetic and genomic resources available in C. elegans, will allow rapid functional assessment of molecules regulating fat storage and lead to a better understanding of their interactions with other fat regulatory pathways.

Public Health Relevance

Studies of fat storage regulation in C. elegans will identify key target genes that modulate fat storage in response to conserved transcriptional regulators and signal transduction pathways. New insights into the mechanisms controlling fat storage will contribute to a broader understanding of the causes and potential treatments of obesity and diabetes.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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Cellular Aspects of Diabetes and Obesity Study Section (CADO)
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Haft, Carol R
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Washington State University
Schools of Arts and Sciences
United States
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Hou, Nicole S; Gutschmidt, Aljona; Choi, Daniel Y et al. (2014) Activation of the endoplasmic reticulum unfolded protein response by lipid disequilibrium without disturbed proteostasis in vivo. Proc Natl Acad Sci U S A 111:E2271-80
Webster, Christopher M; Deline, Marshall L; Watts, Jennifer L (2013) Stress response pathways protect germ cells from omega-6 polyunsaturated fatty acid-mediated toxicity in Caenorhabditis elegans. Dev Biol 373:14-25
Shi, Xun; Li, Juan; Zou, Xiaoju et al. (2013) Regulation of lipid droplet size and phospholipid composition by stearoyl-CoA desaturase. J Lipid Res 54:2504-14
Vrablik, Tracy L; Watts, Jennifer L (2013) Polyunsaturated fatty acid derived signaling in reproduction and development: insights from Caenorhabditis elegans and Drosophila melanogaster. Mol Reprod Dev 80:244-59
Vrablik, Tracy L; Watts, Jennifer L (2012) Emerging roles for specific fatty acids in developmental processes. Genes Dev 26:631-7
Walker, Amy K; Jacobs, Rene L; Watts, Jennifer L et al. (2011) A conserved SREBP-1/phosphatidylcholine feedback circuit regulates lipogenesis in metazoans. Cell 147:840-52
Liang, Bin; Ferguson, Kim; Kadyk, Lisa et al. (2010) The role of nuclear receptor NHR-64 in fat storage regulation in Caenorhabditis elegans. PLoS One 5:e9869
Watts, Jennifer L (2009) Fat synthesis and adiposity regulation in Caenorhabditis elegans. Trends Endocrinol Metab 20:58-65
Brooks, Kyleann K; Liang, Bin; Watts, Jennifer L (2009) The influence of bacterial diet on fat storage in C. elegans. PLoS One 4:e7545
Watts, Jennifer L (2008) Fattening up without overeating. Cell Metab 8:95-6

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