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Polygenic control of Caenorhabditis elegans fat storage

Nature Genetics volume 38, pages 363–368 (2006)Cite this article

Abstract

Tubby mice1 and individuals with Bardet-Biedl syndrome2 have defects in ciliated neuron function and obesity, suggesting an as-yet unknown metabolic signaling axis from ciliated neurons to fat storage tissues. Here we show coordinate regulation of Caenorhabditis elegans fat storage by orthologues of these genes acting in ciliated neurons and by a 3-ketoacyl-coA thiolase (encoded by kat-1) that acts in fat storage tissue. A genetic screen for markedly enhanced fat storage in tub-1 mutants led to the isolation only of kat-1 alleles, which impair fatty acid β-oxidation. kat-1 acts in the intestine, the major C. elegans fat storage tissue, and is transcriptionally upregulated in animals with high fat storage. A genetic screen for synergistic increase in fat storage of a kat-1 mutant identified bbs-1. bbs-1 acts in 15 ciliated neurons that are poised to sense external and internal nutrient levels, supporting a model in which bbs-1 and tub-1 in ciliated neurons form part of an ancient, conserved neuroendocrine axis. This pathway also includes genes encoding intraflagellar transport proteins and cyclic nucleotide gated channels, demonstrating that C. elegans fat storage is under polygenic control.

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Figure 1: Identification of Tub orthologue tub-1 and kat-1 thiolase in C. elegans.
Figure 2: Expression pattern and subcellular localization of KAT-1.
Figure 4: Functional deficit in nine classes of ciliated neurons causes synergistic increase in lipid accumulation in kat-1 mutant animals.
Figure 3: Defects in sensory cilia or their support cells cause a synergistic increase in lipid accumulation in kat-1 mutant animals.

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Acknowledgements

We thank E. O'Rourke and R. Johnston for critical reading of the manuscript; W. Li, K. Ashrafi and Y. Modis for advice; S. Jocksimovic for technical assistance; S. Mitani for the kat-1(tm1037) allele; J. Plotnikova for instructions on confocal microscopy; E. O'Rourke for advice on pharyngeal pumping and food consumption assays; J. Dittman for ttx-3::dsRed; L. Dreier for the antibody against GFP; T. Stiernagle at the C. elegans Genetics Center for providing strains; A. Fire for GFP vectors; M. Vidal for cDNA clones and members of the Ruvkun, Kaplan and Avruch labs for discussion. We also thank J. Spoerke for help with isolating the tub-1 deletion alleles and L. Liu for help with generating the tub-1 rescuing constructs. This work was supported by fellowships from the Human Frontier Science Program and Massachusetts General Hospital Fund for Medical Discovery to H.Y.M. and by grants from the US National Institutes of Health to G.R.

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Author notes

  1. Michael Basson

    Present address: Nature Medicine, 75 Varick Street, New York, New York, 10013, USA

  2. Carl D Johnson

    Present address: Hereditary Disease Foundation, 3960 Broadway, New York, New York, 10032, USA

Authors and Affiliations

  1. Department of Molecular Biology, Massachusetts General Hospital and Department of Genetics, Harvard Medical School Boston, 02114, Massachusetts, USA

    Ho Yi Mak & Gary Ruvkun

  2. Axys Pharmaceuticals, 180 Kimball Way, San Francisco, 94080, California, USA

    Laura S Nelson, Michael Basson & Carl D Johnson

  3. Nature Medicine, 75 Varick Street, New York, New York, 10013, USA

    Carl D Johnson

  4. Hereditary Disease Foundation, 3960 Broadway, New York, New York, 10032, USA

    Michael Basson

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  1. Ho Yi Mak
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Correspondence to Gary Ruvkun.

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The authors declare no competing financial interests.

Supplementary information

Supplementary Fig. 1

Chemosensation and lipid accumulation defects in tub-1 mutant animals. (PDF 187 kb)

Supplementary Fig. 2

Comparison of locomotory behavior of wild-type and mutant animals with altered fat accumulation. (PDF 1200 kb)

Supplementary Fig. 3

Sequence alignment of KAT-1 and its human and yeast orthologues. (PDF 161 kb)

Supplementary Fig. 4

KAT-1, but not its close paralogue, T02G5.7, contains a functional peroxisomal targeting signmal. (PDF 318 kb)

Supplementary Fig. 5

Normal peroxisomal and mitochondrial morphology in kat-1 tub-1 mutant animals. (PDF 1424 kb)

Supplementary Fig. 6

Sequence alignment of C. elegans BBS-1 and human BBS1. (PDF 170 kb)

Supplementary Methods (PDF 118 kb)

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Mak, H., Nelson, L., Basson, M. et al. Polygenic control of Caenorhabditis elegans fat storage. Nat Genet 38, 363–368 (2006). https://doi.org/10.1038/ng1739

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