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Caenorhabditis elegans dauers need LKB1/AMPK to ration lipid reserves and ensure long-term survival

Nature volume 457, pages 210–214 (2009)Cite this article

Abstract

Many organisms can enter a dormant state or diapause to survive harsh environmental conditions for extended durations. When Caenorhabditis elegans larvae enter dauer they arrest feeding but remain active and motile, yet become stress-resistant, extremely long-lived and non-ageing1. Entry into dauer is associated with a reduction in insulin-like signalling, the accumulation of nutritive resources and a concomitant global change in metabolism2,3,4,5, yet the precise molecular and physiological processes that enable long-term survival in the absence of caloric intake remain largely unknown. We show here that C. elegans larvae that lack LKB1/AMPK (AMP-activated protein kinase) signalling enter dauer normally, but then rapidly consume their stored energy and prematurely expire following vital organ failure. We found that this signalling pathway acts in adipose-like tissues to downregulate triglyceride hydrolysis so that these lipid reserves are rationed to last the entire duration of the arrest. Indeed, the downregulation of adipose triglyceride lipase (ATGL-1) activity suppresses both the rapid depletion of stored lipids and reduced life span of AMPK mutant dauers, while AMPK directly phosphorylates ATGL-1. Finally, we show that the slow release of energy during dauer is critical for appropriate long-term osmoregulation, which fails as triglyceride resources become depleted. These mechanisms may be essential for survival through diapause, hibernation, or long-term fasting in diverse organisms and may also underlie AMPK-dependent life span extension.

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Figure 1: aak-2 functions in the hypodermis and excretory system to regulate dauer survival.
Figure 2: aak-2 blocks ATGL-1-mediated triglyceride hydrolysis to ensure long-term dauer survival.
Figure 3: aak-2 is required for proper osmoregulation during dauer.

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References

  1. Klass, M. & Hirsh, D. Non-ageing developmental variant of Caenorhabditis elegans . Nature 260, 523–525 (1976)

    Article  ADS  CAS  PubMed  Google Scholar 

  2. Burnell, A. M., Houthoofd, K., O'Hanlon, K. & Vanfleteren, J. R. Alternate metabolism during the dauer stage of the nematode Caenorhabditis elegans . Exp. Gerontol. 40, 850–856 (2005)

    Article  CAS  PubMed  Google Scholar 

  3. 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  PubMed  Google Scholar 

  4. McElwee, J., Bubb, K. & Thomas, J. H. Transcriptional outputs of the Caenorhabditis elegans forkhead protein DAF-16. Aging Cell 2, 111–121 (2003)

    Article  CAS  PubMed  Google Scholar 

  5. McElwee, J. J., Schuster, E., Blanc, E., Thornton, J. & Gems, D. Diapause-associated metabolic traits reiterated in long-lived daf-2 mutants in the nematode Caenorhabditis elegans . Mech. Ageing Dev. 127, 458–472 (2006)

    Article  CAS  PubMed  Google Scholar 

  6. Kenyon, C., Chang, J., Gensch, E., Rudner, A. & Tabtiang, R. A. C. elegans mutant that lives twice as long as wild type. Nature 366, 461–464 (1993)

    Article  ADS  CAS  PubMed  Google Scholar 

  7. Narbonne, P. & Roy, R. Inhibition of germline proliferation during C. elegans dauer development requires PTEN, LKB1 and AMPK signalling. Development 133, 611–619 (2006)

    Article  CAS  PubMed  Google Scholar 

  8. Hardie, D. G. AMP-activated/SNF1 protein kinases: Conserved guardians of cellular energy. Nature Rev. Mol. Cell Biol. 8, 774–785 (2007)

    Article  CAS  Google Scholar 

  9. Apfeld, J., O'Connor, G., McDonagh, T., DiStefano, P. S. & Curtis, R. The AMP-activated protein kinase AAK-2 links energy levels and insulin-like signals to lifespan in C. elegans . Genes Dev. 18, 3004–3009 (2004)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Fukushige, T., Hendzel, M. J., Bazett-Jones, D. P. & McGhee, J. D. Direct visualization of the elt-2 gut-specific GATA factor binding to a target promoter inside the living Caenorhabditis elegans embryo. Proc. Natl Acad. Sci. USA 96, 11883–11888 (1999)

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  11. Maduro, M. & Pilgrim, D. Identification and cloning of unc-119, a gene expressed in the Caenorhabditis elegans nervous system. Genetics 141, 977–988 (1995)

    CAS  PubMed  PubMed Central  Google Scholar 

  12. Masse, I., Molin, L., Billaud, M. & Solari, F. Lifespan and dauer regulation by tissue-specific activities of Caenorhabditis elegans DAF-18. Dev. Biol. 286, 91–101 (2005)

    Article  CAS  PubMed  Google Scholar 

  13. Okkema, P. G., Harrison, S. W., Plunger, V., Aryana, A. & Fire, A. Sequence requirements for myosin gene expression and regulation in Caenorhabditis elegans . Genetics 135, 385–404 (1993)

    CAS  PubMed  PubMed Central  Google Scholar 

  14. Myers, T. R. & Greenwald, I. lin-35 Rb acts in the major hypodermis to oppose ras-mediated vulval induction in C. elegans . Dev. Cell 8, 117–123 (2005)

    Article  CAS  PubMed  Google Scholar 

  15. McKay, S. J. et al. Gene expression profiling of cells, tissues, and developmental stages of the nematode C. elegans . Cold Spring Harb. Symp. Quant. Biol. 68, 159–169 (2003)

    Article  CAS  PubMed  Google Scholar 

  16. Sherman, T. et al. The abts and sulp families of anion transporters from Caenorhabditis elegans . Am. J. Physiol. Cell Physiol. 289, C341–C351 (2005)

    Article  CAS  PubMed  Google Scholar 

  17. Loria, P. M., Hodgkin, J. & Hobert, O. A conserved postsynaptic transmembrane protein affecting neuromuscular signaling in Caenorhabditis elegans . J. Neurosci. 24, 2191–2201 (2004)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Huang, P. & Stern, M. J. FGF signaling functions in the hypodermis to regulate fluid balance in C. elegans . Development 131, 2595–2604 (2004)

    Article  CAS  PubMed  Google Scholar 

  19. Mello, C. C., Kramer, J. M., Stinchcomb, D. & Ambros, V. Efficient gene transfer in C. elegans: Extrachromosomal maintenance and integration of transforming sequences. EMBO J. 10, 3959–3970 (1991)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. 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  PubMed  Google Scholar 

  21. Schweiger, M. et al. Adipose triglyceride lipase and hormone-sensitive lipase are the major enzymes in adipose tissue triacylglycerol catabolism. J. Biol. Chem. 281, 40236–40241 (2006)

    Article  CAS  PubMed  Google Scholar 

  22. Zimmermann, R. et al. Fat mobilization in adipose tissue is promoted by adipose triglyceride lipase. Science 306, 1383–1386 (2004)

    Article  ADS  CAS  PubMed  Google Scholar 

  23. Gronke, S. et al. Brummer lipase is an evolutionary conserved fat storage regulator in Drosophila . Cell Metab. 1, 323–330 (2005)

    Article  PubMed  Google Scholar 

  24. Gwinn, D. M. et al. AMPK phosphorylation of raptor mediates a metabolic checkpoint. Mol. Cell 30, 214–226 (2008)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Nelson, F. K. & Riddle, D. L. Functional study of the Caenorhabditis elegans secretory-excretory system using laser microsurgery. J. Exp. Zool. 231, 45–56 (1984)

    Article  CAS  PubMed  Google Scholar 

  26. Lamitina, S. T. & Strange, K. Transcriptional targets of DAF-16 insulin signaling pathway protect C. elegans from extreme hypertonic stress. Am. J. Physiol. Cell Physiol. 288, C467–C474 (2005)

    Article  CAS  PubMed  Google Scholar 

  27. Curtis, R., O'Connor, G. & DiStefano, P. S. Aging networks in Caenorhabditis elegans: AMP-activated protein kinase (aak-2) links multiple aging and metabolism pathways. Aging Cell 5, 119–126 (2006)

    Article  CAS  PubMed  Google Scholar 

  28. Greer, E. L. et al. An AMPK-FOXO pathway mediates longevity induced by a novel method of dietary restriction in C. elegans . Curr. Biol. 17, 1646–1656 (2007)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Schulz, T. J. et al. Glucose restriction extends Caenorhabditis elegans life span by inducing mitochondrial respiration and increasing oxidative stress. Cell Metab. 6, 280–293 (2007)

    Article  CAS  PubMed  Google Scholar 

  30. Feng, J., Bussiere, F. & Hekimi, S. Mitochondrial electron transport is a key determinant of life span in Caenorhabditis elegans . Dev. Cell 1, 633–644 (2001)

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

We thank A. Fire, O. Hobert, I. Greenwald, D. Baillie, K. Nehrke, J. McGhee, M. Han, S. Li, E. Colella, M. Hebeisen, J. Ouellet, A. Shingina, M. Maduro, F. Solari, E. Greer, J. Lapointe, W. Yang and S. Hekimi for reagents, strains, constructs, help, advice and support. Some of the strains that were used in this analysis came from the Caenorhabditis Genetic Center (CGC), the C. elegans Gene Knockout Consortium, the Japan National Bioresource Project, and the Genome BC C. elegans Gene Expression Consortium. This work was supported by research grants from the Canadian Cancer Society and the Canadian Institutes of Health Research (CIHR) to R.R. P.N. is a recipient of an NSERC studentship. R.R. is a CIHR New Investigator.

Author Contributions P.N. designed and conducted all the experiments, except the kinase assays, which were performed by R.R.. The manuscript was written by P.N. and edited by R.R.

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  1. Department of Biology, McGill University, Montréal, Québec H3A 1B1, Canada,

    Patrick Narbonne & Richard Roy

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Correspondence to Richard Roy.

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Narbonne, P., Roy, R. Caenorhabditis elegans dauers need LKB1/AMPK to ration lipid reserves and ensure long-term survival. Nature 457, 210–214 (2009). https://doi.org/10.1038/nature07536

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