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Nuclear hormone receptor NHR-49 controls fat consumption and fatty acid composition in C. elegans.

Van Gilst, Marc R and Hadjivassiliou, Haralambos and Jolly, Amber and Yamamoto, Keith R (2005) Nuclear hormone receptor NHR-49 controls fat consumption and fatty acid composition in C. elegans. PLoS biology, 3 (2). e53. ISSN 1545-7885

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Mammalian nuclear hormone receptors (NHRs), such as liver X receptor, farnesoid X receptor, and peroxisome proliferator-activated receptors (PPARs), precisely control energy metabolism. Consequently, these receptors are important targets for the treatment of metabolic diseases, including diabetes and obesity. A thorough understanding of NHR fat regulatory networks has been limited, however, by a lack of genetically tractable experimental systems. Here we show that deletion of the Caenorhabditis elegans NHR gene nhr-49 yielded worms with elevated fat content and shortened life span. Employing a quantitative RT-PCR screen, we found that nhr-49 influenced the expression of 13 genes involved in energy metabolism. Indeed, nhr-49 served as a key regulator of fat usage, modulating pathways that control the consumption of fat and maintain a normal balance of fatty acid saturation. We found that the two phenotypes of the nhr-49 knockout were linked to distinct pathways and were separable: The high-fat phenotype was due to reduced expression of enzymes in fatty acid beta-oxidation, and the shortened adult life span resulted from impaired expression of a stearoyl-CoA desaturase. Despite its sequence relationship with the mammalian hepatocyte nuclear factor 4 receptor, the biological activities of nhr-49 were most similar to those of the mammalian PPARs, implying an evolutionarily conserved role for NHRs in modulating fat consumption and composition. Our findings in C. elegans provide novel insights into how NHR regulatory networks are coordinated to govern fat metabolism.

Item Type: Article or Abstract
DOI: 10.1371/journal.pbio.0030053
PubMed ID: 15719061
PMCID: PMC547972
Grant Numbers: NIH K01 DK61361–01
Keywords or MeSH Headings: Animals; Caenorhabditis elegans/genetics/metabolism; Caenorhabditis elegans Proteins/genetics/metabolism; Energy Metabolism/genetics; Fatty Acids/chemistry/metabolism; Mitochondria/genetics/metabolism; Receptors, Cytoplasmic and Nuclear/chemistry/genetics/metabolism;
Subjects: Cellular and Organismal Processes > Metabolism
Molecules > Proteins > Receptors
Cellular and Organismal Processes > Genetic processes > Transcription
Depositing User: Library Staff
Date Deposited: 30 Sep 2008 18:57
Last Modified: 13 May 2010 22:19

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