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Drosophila dFOXO controls lifespan and regulates insulin signalling in brain and fat body

Nature volume 429, pages 562–566 (2004)Cite this article

A Corrigendum to this article was published on 03 March 2005

Abstract

In Drosophila melanogaster, ageing is slowed when insulin-like signalling is reduced: life expectancy is extended by more than 50% when the insulin-like receptor (InR) or its receptor substrate (chico) are mutated, or when insulin-producing cells are ablated1,2,3. But we have yet to resolve when insulin affects ageing, or whether insulin signals regulate ageing directly or indirectly through secondary hormones. Caenorhabditis elegans lifespan is also extended when insulin signalling is inhibited in certain tissues, or when repressed in adult worms4,5, and this requires the forkhead transcription factor (FOXO) encoded by daf-16 (ref. 6). The D. melanogaster insulin-like receptor mediates phosphorylation of dFOXO, the equivalent of nematode daf-16 and mammalian FOXO3a7,8. We demonstrate here that dFOXO regulates D. melanogaster ageing when activated in the adult pericerebral fat body. We further show that this limited activation of dFOXO reduces expression of the Drosophila insulin-like peptide dilp-2 synthesized in neurons, and represses endogenous insulin-dependent signalling in peripheral fat body. These findings suggest that autonomous and non-autonomous roles of insulin signalling combine to control ageing.

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Figure 1: Survivorship and stress resistance in adults with tissue-specific expression of dFOXO or dPTEN.
Figure 2: Tissue distribution of fat body drivers S132 and S1106.
Figure 3: Cellular localization of dFOXO in head and abdominal fat body.
Figure 4: The abundance and systemic impact of neuronal dilp mRNA in response to dFOXO expressed in head fat body.

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Acknowledgements

We thank F. Lemieux, A. Bentle, M. Duon and M. Zerofsky for technical support, and A. Brunet, J. Wasserman, B. Edgar, G. Roman, O. Puig and T. Osterwalder for materials. This work was supported by the National Institute of Health (Institute of Aging), the American Federation of Aging Research, the Ellison Medical Foundation and a collaborative research grant from Pfizer.

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Authors and Affiliations

  1. Division of Biology and Medicine, Box G-W, Brown University, Providence, Rhode Island, 02912, USA

    Dae Sung Hwangbo, Boris Gersham, Meng-Ping Tu, Michael Palmer & Marc Tatar

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  1. Dae Sung Hwangbo
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  3. Meng-Ping Tu
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Correspondence to Marc Tatar.

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Supplementary information

Supplementary Figure S1

Expression of exogenous dFOXO in the eye disc reduces growth. We verify that our transformed strains produce eye growth phenotypes similar to those reported by previously published strains with UAS-FOXO. We test several independent inserts of both the wildtype dFOXO and the phosphorylation site mutant dFOXO-TM. We also demonstrate that our mifepristone feeding protocol induces the expected expression patterns with ELAV-{PSwitch}.

Supplementary Figure S2

These trials show that feeding mifepristone in yeast paste has no effect on survival or males or females. Data are presented to show that expression of dFOXO-TM in the head fat body, which increases longevity, does not alter gross fecundity.

Supplementary Figure S3 Legend

Supplementary Figure S3

This series of cryosection images show that induction of exogenous dFOXO-TM in the abdominal fat body is effective but does not cause a change in the endogenous dFOXO of the head fat body.

Supplementary Figure S4

Abundance of dilp mRNA from head measured by microarray. Insulin producing cells of adults are in the brain; dFOXO-TM was induced in the pericerebral fat body and produced a small but significant decrease in dilp2 from these neurons. These array data are refined and verified by real-time PCR analysis in the full text.

Supplementary Figure S5

The driver S32 is restricted to expression in the adult head. Using primers for sequence specific to the exogenous dFOXO-TM, message is detected in cDNA from head tissue and not from abdominal tissue.

Supplementary Table S1

When expressed through larval stages with broadly active drivers, dFOXO wildtype and phosphorylation mutant are lethal.

Supplementary Table S2

Summary of life table statistics for demographic trials with fat body and CNS-related mifepristone activated drivers directed at dFOXO, dFOXO-TM and PTEN. Data are given for male and females, and for the wildtype control trial plotted in Supplementary Figure 2.

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Hwangbo, D., Gersham, B., Tu, MP. et al. Drosophila dFOXO controls lifespan and regulates insulin signalling in brain and fat body. Nature 429, 562–566 (2004). https://doi.org/10.1038/nature02549

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