Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Letter
  • Published:

Genome-wide RNAi analysis of Caenorhabditis elegans fat regulatory genes

Nature volume 421, pages 268–272 (2003)Cite this article

Abstract

Regulation of body fat storage involves signalling between centres that regulate feeding in the brain and sites of fat storage and use in the body1,2. Here we describe an assay for analysing fat storage and mobilization in living Caenorhabditis elegans. By using RNA-mediated interference (RNAi)3,4 to disrupt the expression of each of the 16,757 worm genes, we have systematically screened the C. elegans genome for genes necessary for normal fat storage. We identify 305 gene inactivations that cause reduced body fat and 112 gene inactivations that cause increased fat storage. Analysis of the fat-reducing gene inactivations in insulin, serotonin and tubby signalling mutants of C. elegans, which have increased body fat, identifies a core set of fat regulatory genes as well as pathway-specific fat regulators. Many of the newly identified worm fat regulatory genes have mammalian homologues, some of which are known to function in fat regulation. Other C. elegans fat regulatory genes that are conserved across animal phylogeny, but have not previously been implicated in fat storage, may point to ancient and universal features of fat storage regulation, and identify targets for treating obesity and its associated diseases.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Changes in fat content in known mutants can be detected by Nile Red staining.
Figure 2: Examples of RNAi targets that produce alterations in fat content.

Similar content being viewed by others

References

  1. Schwartz, M. W., Woods, S. C., Porte, D. Jr, Seeley, R. J. & Baskin, D. G. Central nervous system control of food intake. Nature 404, 661–671 (2000)

    Article  CAS  Google Scholar 

  2. Friedman, J. M. & Halaas, J. L. Leptin and the regulation of body weight in mammals. Nature 395, 763–770 (1998)

    Article  ADS  CAS  Google Scholar 

  3. Fire, A. et al. Potent and specific genetic interference by double-stranded RNA in Caenorhabditis elegans. Nature 391, 806–811 (1998)

    Article  ADS  CAS  Google Scholar 

  4. Kamath, R. S. et al. Systematic functional analysis of the Caenorhabditis elegans genome using RNAi. Nature 421, 231–237 (2003)

    Article  ADS  CAS  Google Scholar 

  5. Greenspan, P. & Fowler, S. D. Spectrofluorometric studies of the lipid probe, Nile Red. J. Lipid Res. 26, 781–789 (1985)

    CAS  Google Scholar 

  6. Kimura, K. D., Tissenbaum, H. A., Liu, Y. & Ruvkun, G. daf-2, an insulin receptor-like gene that regulates longevity and diapause in Caenorhabditis elegans. Science 277, 942–946 (1997)

    Article  CAS  Google Scholar 

  7. Riddle, D. L. & Albert, P. S. C. elegans II (eds Riddle, D. L., Blumenthal, T., Meyer, B. J. & Priess, J. R.) 739–768 (Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY, 1997)

    Google Scholar 

  8. Wadsworth, W. G. & Riddle, D. L. Developmental regulation of energy metabolism in Caenorhabditis elegans. Dev. Biol. 132, 167–173 (1989)

    Article  CAS  Google Scholar 

  9. Ogg, S. et al. The Fork head transcription factor DAF-16 transduces insulin-like metabolic and longevity signals in C. elegans. Nature 389, 994–999 (1997)

    Article  ADS  CAS  Google Scholar 

  10. Lin, K. et al. An HNF-3/forkhead family member that can function to double the life-span of Caenorhabditis elegans. Science 278, 1319–1322 (1997)

    Article  ADS  CAS  Google Scholar 

  11. Ogg, S. & Ruvkun, G. The C. elegans PTEN homolog, DAF-18, acts in the insulin receptor-like metabolic signaling pathway. Mol. Cell 2, 887–893 (1998)

    Article  CAS  Google Scholar 

  12. Tecott, L. H. et al. Eating disorder and epilepsy in mice lacking 5-HT2c serotonin receptors. Nature 374, 542–546 (1995)

    Article  ADS  CAS  Google Scholar 

  13. Noben-Trauth, K., Naggert, J. K., North, M. A. & Nishina, P. M. A candidate gene for the mouse mutation tubby. Nature 380, 534–538 (1996)

    Article  ADS  CAS  Google Scholar 

  14. Sze, J. Y., Victor, M., Loer, C., Shi, Y. & Ruvkun, G. Food and metabolic signalling defects in a Caenorhabditis elegans serotonin-synthesis mutant. Nature 403, 560–564 (2000)

    Article  ADS  CAS  Google Scholar 

  15. Liu, L. X. et al. High-throughput isolation of Caenorhabditis elegans deletion mutants. Genome Res. 9, 859–867 (1999)

    Article  CAS  Google Scholar 

  16. Kamath, R. S., Martinez-Campos, M., Zipperlen, P., Fraser, A. G. & Ahringer, J. Effectiveness of specific RNA-mediated interference through ingested double-stranded RNA in Caenorhabditis elegans. Genome Biol. 2, 1–10 (2000)

    Article  Google Scholar 

  17. Brown, M. S. & Goldstein, J. L. A proteolytic pathway that controls the cholesterol content of membranes, cells, and blood. Proc. Natl Acad. Sci. USA 96, 11041–11048 (1999)

    Article  ADS  CAS  Google Scholar 

  18. Rolland, V. et al. Evidence of increased glyceraldehyde-3-phosphate dehydrogenase and fatty acid synthetase promoter activities in transiently transfected adipocytes from genetically obese rats. J. Biol. Chem. 270, 1102–1106 (1995)

    Article  CAS  Google Scholar 

  19. Olswang, Y. et al. A mutation in the peroxisome proliferator-activated receptor γ binding site in the gene for the cytosolic form of phosphoenolpyruvate carboxykinase reduces adipose tissue size and fat content in mice. Proc. Natl Acad. Sci. USA 99, 625–630 (2002)

    Article  ADS  CAS  Google Scholar 

  20. Adibi, S. A. The oligopeptide transporter (Pept-1) in human intestine: biology and function. Gastroenterology 113, 332–340 (1997)

    Article  CAS  Google Scholar 

  21. Chawla, A., Repa, J. J., Evans, R. M. & Mangelsdorf, D. J. Nuclear receptors and lipid physiology: opening the X-files. Science 294, 1866–1870 (2001)

    Article  ADS  CAS  Google Scholar 

  22. Yamagata, K. et al. Mutations in the hepatocyte nuclear factor-4α gene in maturity-onset diabetes of the young (MODY1). Nature 384, 458–460 (1996)

    Article  ADS  CAS  Google Scholar 

  23. Good, D. J. et al. Hypogonadism and obesity in mice with a targeted deletion of the Nhlh2 gene. Nature Genet 15, 397–401 (1997)

    Article  CAS  Google Scholar 

  24. Apfeld, J. & Kenyon, C. Regulation of lifespan by sensory perception in Caenorhabditis elegans. Nature 402, 804–809 (1999)

    Article  ADS  CAS  Google Scholar 

  25. Wolkow, C. A., Kimura, K. D., Lee, M. S. & Ruvkun, G. Regulation of C. elegans life-span by insulin-like signaling in the nervous system. Science 290, 147–150 (2000)

    Article  ADS  CAS  Google Scholar 

  26. Brockmann, G. A. & Bevoval, M. R. Using mouse models to dissect the genetics of obesity. Trends Genet. 18, 367–376 (2002)

    Article  CAS  Google Scholar 

  27. Brenner, S. The genetics of Caenorhabditis elegans. Genetics 77, 71–94 (1974)

    CAS  Google Scholar 

  28. Johnstone, I. L. C. elegans: A Practical Approach (ed. Hope, I. A.) 201–225 (Oxford Univ. Press, Oxford, 1999)

    Google Scholar 

  29. Watts, J. L. & Browse, J. Genetic dissection of polyunsaturated fatty acid synthesis in Caenorhabditis elegans. Proc. Natl Acad. Sci. USA 99, 5854–5859 (2002)

    Article  ADS  CAS  Google Scholar 

Download references

Acknowledgements

We thank M. Basson and C. Johnson for the tub-1(nr2004) strain. K.A is grateful to A. Pasquinelli and other members of the Ruvkun laboratory for discussions and suggestions. K.A. was supported by a fellowship from the Damon-Runyon Walter-Winchell Cancer Research Fund; J.W. by a NIH grant; A.G.F. by a US Army Breast Cancer Research Fellowship; R.S.K. by a Howard Hughes Medical Institute Predoctoral Fellowship; and J.A. by a Wellcome Trust Senior Research Fellowship.

Author information

Authors and Affiliations

  1. Department of Molecular Biology, Massachusetts General Hospital, Boston, Massachusetts, 02114, USA

    Kaveh Ashrafi, Francesca Y. Chang & Gary Ruvkun

  2. Department of Genetics, Harvard Medical School, Boston, Massachusetts, 02114, USA

    Kaveh Ashrafi & Gary Ruvkun

  3. Institute of Biological Chemistry, Washington State University, Pullman, Washington, 99164, USA

    Jennifer L. Watts

  4. Wellcome/Cancer Research UK Institute, University of Cambridge, Tennis Court Road, CB2 IQR, Cambridge, UK

    Andrew G. Fraser, Ravi S. Kamath & Julie Ahringer

Authors
  1. Kaveh Ashrafi
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Francesca Y. Chang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Jennifer L. Watts
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Andrew G. Fraser
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Ravi S. Kamath
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Julie Ahringer
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Gary Ruvkun
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Gary Ruvkun.

Ethics declarations

Competing interests

The authors declare that they have no competing financial interests.

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Cite this article

Ashrafi, K., Chang, F., Watts, J. et al. Genome-wide RNAi analysis of Caenorhabditis elegans fat regulatory genes. Nature 421, 268–272 (2003). https://doi.org/10.1038/nature01279

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nature01279

This article is cited by

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing