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Abstract

Hypothalamic pro-opiomelanocortin (POMC) neurons promote satiety. Cannabinoid receptor 1 (CB1R) is critical for the central regulation of food intake. Here we test whether CB1R-controlled feeding in sated mice is paralleled by decreased activity of POMC neurons. We show that chemical promotion of CB1R activity increases feeding, and notably, CB1R activation also promotes neuronal activity of POMC cells. This paradoxical increase in POMC activity was crucial for CB1R-induced feeding, because designer-receptors-exclusively-activated-by-designer-drugs (DREADD)-mediated inhibition of POMC neurons diminishes, whereas DREADD-mediated activation of POMC neurons enhances CB1R-driven feeding. The Pomc gene encodes both the anorexigenic peptide α-melanocyte-stimulating hormone, and the opioid peptide β-endorphin. CB1R activation selectively increases β-endorphin but not α-melanocyte-stimulating hormone release in the hypothalamus, and systemic or hypothalamic administration of the opioid receptor antagonist naloxone blocks acute CB1R-induced feeding. These processes involve mitochondrial adaptations that, when blocked, abolish CB1R-induced cellular responses and feeding. Together, these results uncover a previously unsuspected role of POMC neurons in the promotion of feeding by cannabinoids.

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Change history

  • Corrected online 04 March 2015

    Minor changes were made to citations in the Methods.

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Acknowledgements

The authors thank M. Shanabrough and J. Bober for technical support and R. Jakab for assisting with the illustrations. This work was supported by the US National Institutes of Health (DP1 DK098058, R01 DK097566, R01 AG040236 and P01 NS062686), the American Diabetes Association, The Klarmann Family Foundation, the Helmholtz Society (ICEMED) and the Deutsche Forschungsgemeinschaft SFB 1052/1 (Obesity Mechanisms).

Author information

Author notes

    • Jae Geun Kim

    Present address: Division of Life Sciences, College of Life Sciences and Bioengineering, Incheon National University, Incheon 406-772, South Korea.

Affiliations

  1. Program in Integrative Cell Signaling and Neurobiology of Metabolism, Section of Comparative Medicine, Yale University School of Medicine, New Haven, Connecticut 06520, USA

    • Marco Koch
    • , Luis Varela
    • , Jae Geun Kim
    • , Jung Dae Kim
    • , Francisco Hernández-Nuño
    • , Klara Szigeti-Buck
    • , Marcelo O. Dietrich
    • , Xiao-Bing Gao
    • , Sabrina Diano
    •  & Tamas L. Horvath
  2. Institute of Anatomy, University of Leipzig, 04103 Leipzig, Germany

    • Marco Koch
    •  & Ingo Bechmann
  3. Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, New Haven, Connecticut 06520, USA

    • Jung Dae Kim
    • , Sabrina Diano
    •  & Tamas L. Horvath
  4. Obesity & Diabetes Institute, Department of Physiology, Monash University, Clayton, Victoria 3800, Australia

    • Stephanie E. Simonds
    •  & Michael A. Cowley
  5. Division of Endocrinology & Metabolism, Department of Internal Medicine, The University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA

    • Carlos M. Castorena
    • , Claudia R. Vianna
    •  & Joel K. Elmquist
  6. Department of Neurobiology, Yale University School of Medicine, New Haven, Connecticut 06520, USA

    • Yury M. Morozov
    • , Pasko Rakic
    • , Marcelo O. Dietrich
    • , Sabrina Diano
    •  & Tamas L. Horvath
  7. Kavli Institute for Neuroscience, Yale University School of Medicine, New Haven, Connecticut 06520, USA

    • Pasko Rakic
    •  & Tamas L. Horvath

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Contributions

M.K., S.D. and T.L.H. developed the conceptual framework of this study. M.K., M.O.D., X.-B.G., S.D. and T.L.H. interpreted results. M.K. performed experiments and analysed results. Experimental contributions: L.V. contributed to Figs 4h–j, 5d and Extended Data Figs 1b, 5e and 6a, b; J.G.K. contributed to Figs 2e, f, 3i, 5a, b and Extended Data Fig. 2g; J.D.K. contributed to Figs 3b–d, 5e–g and Extended Data Figs 5c and 6c; F.H. contributed to Figs 4a, 5c and Extended Data Fig. 5a, b, d; S.E.S. contributed to Fig. 3a; C.M.C., C.R.V. and J.K.E. provided key animal models; Y.M.M. and P.R. contributed to Fig. 3b and Extended Data Fig. 1c; P.R., I.B. and M.A.C. provided materials, animals and equipment; K.S.-B. contributed to Figs 3f and 4d–g; X.-B.G. contributed to Figs 1C, Da–c and 3j. M.K. and T.L.H. wrote the paper.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Tamas L. Horvath.

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DOI

https://doi.org/10.1038/nature14260

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