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A whole-organism screen identifies new regulators of fat storage

Nature Chemical Biology volume 7, pages 206–213 (2011)Cite this article

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Abstract

The regulation of energy homeostasis integrates diverse biological processes ranging from behavior to metabolism and is linked fundamentally to numerous disease states. To identify new molecules that can bypass homeostatic compensatory mechanisms of energy balance in intact animals, we screened for small-molecule modulators of Caenorhabditis elegans fat content. We report on several molecules that modulate fat storage without obvious deleterious effects on feeding, growth and reproduction. A subset of these compounds also altered fat storage in mammalian and insect cell culture. We found that one of the newly identified compounds exerts its effects in C. elegans through a pathway that requires previously undescribed functions of an AMP-activated kinase catalytic subunit and a transcription factor previously unassociated with fat regulation. Thus, our strategy identifies small molecules that are effective within the context of intact animals and reveals relationships between new pathways that operate across phyla to influence energy homeostasis.

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Figure 1: Pharmacological modulation of Nile Red staining in C. elegans.
Figure 2: Fat metabolism in C. elegans is modulated by diverse compounds.
Figure 3: Compounds that lower Nile Red staining in C. elegans modulate lipid accumulation in mammalian and insect cell culture models of adipogenesis and lipid uptake.
Figure 4: The fat phenotype induced by F17 requires an AMPK complex containing the catalytic subunit encoded by aak-1.
Figure 5: Loss of K08F8.2 partially suppresses the F17 low-fat phenotype.
Figure 6: F17 activates the AMPK pathway and reduces the number of lipid droplets in HepG2 hepatocarcinoma cells.

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Acknowledgements

We are grateful to D. Lum for his help and advice with the initial C. elegans experiments. We are thankful to B. Mullaney and K. Cunningham for helpful discussions and comments on the manuscript. We thank K. Thorn and the Nikon Imaging Center for use of the Nikon 6D automated epifluorescence microscope and help with imaging as well as the Small Molecule Discovery Center at the University of California, San Francisco, for providing the small-molecule library. This work was supported by grants from the US National Cancer Institute and US National Institute of Environmental Health Sciences (ES012801, ES019458 and CA056721) to Z.W., the US National Institute of Diabetes and Digestive and Kidney Diseases (DK070149) to K.A., the US National Institute of General Medicine (GM081863) to R.J.B. and a Byers Award to K.A. and R.J.B.

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Author notes

  1. Kaveh Ashrafi and Zena Werb: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Anatomy, University of California, San Francisco, San Francisco, California, USA

    George A Lemieux & Zena Werb

  2. Department of Physiology, University of California, San Francisco, San Francisco, California, USA

    Jason Liu & Kaveh Ashrafi

  3. Department of Anesthesia, University of California, San Francisco, San Francisco, California, USA

    Nasima Mayer & Roland J Bainton

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  1. George A Lemieux
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Contributions

G.A.L., K.A. and Z.W. conceived the study design. G.A.L., J.L. and N.M. performed the experiments. G.A.L., K.A., R.J.B. and Z.W. analyzed the data. G.A.L., K.A. and Z.W. wrote the paper. All the authors read, revised and approved the manuscript.

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Correspondence to Kaveh Ashrafi or Zena Werb.

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Lemieux, G., Liu, J., Mayer, N. et al. A whole-organism screen identifies new regulators of fat storage. Nat Chem Biol 7, 206–213 (2011). https://doi.org/10.1038/nchembio.534

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