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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK074114-07
Application #
8308622
Study Section
Cellular Aspects of Diabetes and Obesity Study Section (CADO)
Program Officer
Haft, Carol R
Project Start
2006-02-01
Project End
2014-08-31
Budget Start
2012-09-01
Budget End
2013-08-31
Support Year
7
Fiscal Year
2012
Total Cost
$307,110
Indirect Cost
$101,685
Name
Washington State University
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
041485301
City
Pullman
State
WA
Country
United States
Zip Code
99164
Shi, Xun; Tarazona, Pablo; Brock, Trisha J et al. (2016) A Caenorhabditis elegans model for ether lipid biosynthesis and function. J Lipid Res 57:265-75
Watts, Jennifer L (2016) Using Caenorhabditis elegans to Uncover Conserved Functions of Omega-3 and Omega-6 Fatty Acids. J Clin Med 5:
Ding, Wei; Smulan, Lorissa J; Hou, Nicole S et al. (2015) s-Adenosylmethionine Levels Govern Innate Immunity through Distinct Methylation-Dependent Pathways. Cell Metab 22:633-45
Vrablik, Tracy L; Petyuk, Vladislav A; Larson, Emily M et al. (2015) Lipidomic and proteomic analysis of Caenorhabditis elegans lipid droplets and identification of ACS-4 as a lipid droplet-associated protein. Biochim Biophys Acta 1851:1337-45
Deline, Marshall; Keller, Julia; Rothe, Michael et al. (2015) Epoxides Derived from Dietary Dihomo-Gamma-Linolenic Acid Induce Germ Cell Death in C. elegans. Sci Rep 5:15417
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
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
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
Deline, Marshall L; Vrablik, Tracy L; Watts, Jennifer L (2013) Dietary supplementation of polyunsaturated fatty acids in Caenorhabditis elegans. J Vis Exp :
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

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