Letter abstract
Nature Medicine 14, 1112 - 1117 (2008)
Published online: 31 August 2008 | doi:10.1038/nm.1866
The Creb1 coactivator Crtc1 is required for energy balance and fertility
Judith Y Altarejos1, Naomi Goebel1, Michael D Conkright2, Hiroshi Inoue1, Jianxin Xie3, Carlos M Arias4, Paul E Sawchenko4 & Marc Montminy1
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.
- Peptide Biology Laboratories, The Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, California 92037, USA.
- The Scripps Research Institute, 5353 Parkside Drive, Jupiter, Florida 33458, USA.
- Cell Signaling Technology, 3 Trask Lane, Danvers, Massachusetts 01923, USA.
- Laboratory of Neuronal Structure and Function, The Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, California 92037, USA.
Correspondence to: Marc Montminy1 e-mail: montminy@salk.edu
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