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The Creb1 coactivator Crtc1 is required for energy balance and fertility

Nature Medicine volume 14, pages 1112–1117 (2008)Cite this article

Abstract

The adipocyte-derived hormone leptin maintains energy balance by acting on hypothalamic leptin receptors (Leprs) that act on the signal transducer and activator of transcription 3 (Stat3)1,2,3,4. Although disruption of Lepr-Stat3 signaling promotes obesity in mice, other features of Lepr function, such as fertility, seem normal, pointing to the involvement of additional regulators. Here we show that the cyclic AMP responsive element–binding protein-1 (Creb1)-regulated transcription coactivator-1 (Crtc1) is required for energy balance and reproduction—Crtc1−/− mice are hyperphagic, obese and infertile. Hypothalamic Crtc1 was phosphorylated and inactive in leptin-deficient ob/ob mice, while leptin administration increased amounts of dephosphorylated nuclear Crtc1. Dephosphorylated Crtc1 stimulated expression of the Cartpt and Kiss1 genes, which encode hypothalamic neuropeptides that mediate leptin's effects on satiety and fertility5,6,7. Crtc1 overexpression in hypothalamic cells increased Cartpt and Kiss1 gene expression, whereas Crtc1 depletion decreased it. Indeed, leptin enhanced Crtc1 activity over the Cartpt and Kiss1 promoters in cells overexpressing Lepr, and these effects were disrupted by expression of a dominant-negative Creb1 polypeptide. As leptin administration increased recruitment of hypothalamic Crtc1 to Cartpt and Kiss1 promoters, our results indicate that the Creb1-Crtc1 pathway mediates the central effects of hormones and nutrients on energy balance and fertility.

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Figure 1: Mice with a knockout of Crtc1 are obese and infertile.
Figure 2: Crtc1−/− mice are hyperphagic and have reduced energy expenditure.
Figure 3: Reduced hypothalamic expression of anorexigenic and reproductive neuropeptide genes in Crtc1−/− mice.
Figure 4: Crtc1 regulates hypothalamic Cartpt and Kiss1 gene expression.

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Acknowledgements

We thank M. Myers (University of Michigan School of Medicine) for leptin receptor expression plasmid, P. Mellon (University of California at San Diego) for mouse GT1-7 hypothalamic cells and M. Kuhar (Emory University School of Medicine) for Cartpt-luciferase reporter. This work was supported by the US National Institutes of Health (DK049777) the Foundation for Medical Research and the Keickhefer Foundation.

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Authors and Affiliations

  1. Peptide Biology Laboratories, The Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, 92037, California, USA

    Judith Y Altarejos, Naomi Goebel, Hiroshi Inoue & Marc Montminy

  2. The Scripps Research Institute, 5353 Parkside Drive, Jupiter, 33458, Florida, USA

    Michael D Conkright

  3. Cell Signaling Technology, 3 Trask Lane, Danvers, 01923, Massachusetts, USA

    Jianxin Xie

  4. Laboratory of Neuronal Structure and Function, The Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, 92037, California, USA

    Carlos M Arias & Paul E Sawchenko

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  1. Judith Y Altarejos
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Contributions

J.Y.A., M.D.C., H.I., P.E.S. and M.M. contributed to the experimental design of this study. J.Y.A., M.D.C., H.I. and C.M.A. performed the mouse experiments. J.Y.A. and N.G. conducted cell culture and biochemical analyses. J.Y.A., N.G. and C.M.A. performed the immunohistochemical staining and in situ hybridization experiments. M.D.C. and J.X. developed the Crtc1 and pCrtc1 (Ser151) antisera, respectively. J.Y.A., N.G. and H.I. analyzed the data. M.M. and J.Y.A. wrote the manuscript.

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Correspondence to Marc Montminy.

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Altarejos, J., Goebel, N., Conkright, M. et al. The Creb1 coactivator Crtc1 is required for energy balance and fertility. Nat Med 14, 1112–1117 (2008). https://doi.org/10.1038/nm.1866

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