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UCP2 mediates ghrelin’s action on NPY/AgRP neurons by lowering free radicals

Author

Listed:
  • Zane B. Andrews

    (Section of Comparative Medicine and Departments of,
    Obstetrics, Gynecology & Reproductive Sciences)

  • Zhong-Wu Liu

    (Obstetrics, Gynecology & Reproductive Sciences
    Yunyang Medical College, Shiyan, Hubei 442000, China)

  • Nicholas Walllingford

    (Obstetrics, Gynecology & Reproductive Sciences)

  • Derek M. Erion

    (Obstetrics, Gynecology & Reproductive Sciences)

  • Erzsebet Borok

    (Obstetrics, Gynecology & Reproductive Sciences)

  • Jeffery M. Friedman

    (Laboratory of Molecular Genetics, Howard Hughes Medical Institute, Rockefeller University, New York, New York 10021, USA)

  • Matthias H. Tschöp

    (University of Cincinnati, Cincinnati, Ohio 45237, USA)

  • Marya Shanabrough

    (Obstetrics, Gynecology & Reproductive Sciences)

  • Gary Cline

    (Internal Medicine, Howard Hughes Medical Institute and,)

  • Gerald I. Shulman

    (Internal Medicine, Howard Hughes Medical Institute and,)

  • Anna Coppola

    (Obstetrics, Gynecology & Reproductive Sciences)

  • Xiao-Bing Gao

    (Obstetrics, Gynecology & Reproductive Sciences)

  • Tamas L. Horvath

    (Section of Comparative Medicine and Departments of,
    Obstetrics, Gynecology & Reproductive Sciences
    Neurobiology, Yale University School of Medicine, New Haven, Connecticut 06520, USA)

  • Sabrina Diano

    (Obstetrics, Gynecology & Reproductive Sciences
    Neurobiology, Yale University School of Medicine, New Haven, Connecticut 06520, USA)

Abstract

The gut-derived hormone ghrelin exerts its effect on the brain by regulating neuronal activity. Ghrelin-induced feeding behaviour is controlled by arcuate nucleus neurons that co-express neuropeptide Y and agouti-related protein (NPY/AgRP neurons). However, the intracellular mechanisms triggered by ghrelin to alter NPY/AgRP neuronal activity are poorly understood. Here we show that ghrelin initiates robust changes in hypothalamic mitochondrial respiration in mice that are dependent on uncoupling protein 2 (UCP2). Activation of this mitochondrial mechanism is critical for ghrelin-induced mitochondrial proliferation and electric activation of NPY/AgRP neurons, for ghrelin-triggered synaptic plasticity of pro-opiomelanocortin-expressing neurons, and for ghrelin-induced food intake. The UCP2-dependent action of ghrelin on NPY/AgRP neurons is driven by a hypothalamic fatty acid oxidation pathway involving AMPK, CPT1 and free radicals that are scavenged by UCP2. These results reveal a signalling modality connecting mitochondria-mediated effects of G-protein-coupled receptors on neuronal function and associated behaviour.

Suggested Citation

  • Zane B. Andrews & Zhong-Wu Liu & Nicholas Walllingford & Derek M. Erion & Erzsebet Borok & Jeffery M. Friedman & Matthias H. Tschöp & Marya Shanabrough & Gary Cline & Gerald I. Shulman & Anna Coppola , 2008. "UCP2 mediates ghrelin’s action on NPY/AgRP neurons by lowering free radicals," Nature, Nature, vol. 454(7206), pages 846-851, August.
    • Handle: RePEc:nat:nature:v:454:y:2008:i:7206:d:10.1038_nature07181
    DOI: 10.1038/nature07181
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    Cited by:

    1. Nathan L. Price & Pablo Fernández-Tussy & Luis Varela & Magdalena P. Cardelo & Marya Shanabrough & Binod Aryal & Rafael Cabo & Yajaira Suárez & Tamas L. Horvath & Carlos Fernández-Hernando, 2024. "microRNA-33 controls hunger signaling in hypothalamic AgRP neurons," Nature Communications, Nature, vol. 15(1), pages 1-13, December.
    2. Yating Liu & Qian Li & Guojing Tian & Xinyi Zhou & Panpan Chen & Bo Chen & Zhao Shan & Bin Qi, 2024. "Neuronal PRDX-2-Mediated ROS Signaling Regulates Food Digestion via peripheral UPRmt Activation," Nature Communications, Nature, vol. 15(1), pages 1-15, December.
    3. Sarah M. Mohr & Rafael Dai Pra & Maryann P. Platt & Viktor V. Feketa & Marya Shanabrough & Luis Varela & Ashley Kristant & Haoran Cao & Dana K. Merriman & Tamas L. Horvath & Sviatoslav N. Bagriantsev , 2024. "Hypothalamic hormone deficiency enables physiological anorexia in ground squirrels during hibernation," Nature Communications, Nature, vol. 15(1), pages 1-15, December.
    4. Lihong Yan & Xin Zhang & Liling Jin & Yin Li & Yang Chen & Jubiao Zhang & Zhenning Sun & Junxia Qi & Changqing Qu & Guanzhong Dong & Yongjie Zhang & Qin Jiang & An Liu & Juxue Li, 2025. "The ARCCRABP1 neurons play a crucial role in the regulation of energy homeostasis," Nature Communications, Nature, vol. 16(1), pages 1-16, December.

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