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Role of melanocortinergic neurons in feeding and the agouti obesity syndrome

Author

Listed:
  • Wei Fan

    (The Vollum Institute for Advanced Biomedical Research)

  • Bruce A. Boston

    (The Vollum Institute for Advanced Biomedical Research
    Oregon Health Sciences University)

  • Robert A. Kesterson

    (The Vollum Institute for Advanced Biomedical Research)

  • Victor J. Hruby

    (University of Arizona)

  • Roger D. Cone

    (The Vollum Institute for Advanced Biomedical Research)

Abstract

DOMINANT alleles at the agouti locus (A) cause an obesity syndrome in the mouse, as a consequence of ectopic expression of the agouti peptide1–6. This peptide, normally only found in the skin, is a high-affinity antagonist of the melanocyte-stimulating hormone receptor (MC1-R)7, thus explaining the inhibitory effect of agouti on eumelanin pigment synthesis. The agouti peptide is also an antagonist of the hypothalamic melanocortin-4 receptor (MC4-R)7–9. To test the hypothesis that agouti causes obesity by antagonism of hypothalamic melanocortin receptors7, we identified cyclic melanocortin analogues10 that are potent agonists or antagonists of the neural MC3 (refs 11, 12) and MC4 receptors. Intracerebroventricular administration of the agonist, MTII, inhibited feeding in four models of hyperphagia: fasted C57BL/6J, ob/ob, and AY mice, and mice injected with neuropeptide Y. Co-administration of the specific melanocortin antagonist and agouti-mimetic SHU9119 completely blocked this inhibition. Furthermore, administration of SHU9119 significantly enhanced nocturnal feeding, or feeding stimulated by a prior fast. Our data show that melanocortinergic neurons exert a tonic inhibition of feeding behaviour. Chronic disruption of this inhibitory signal is a likely explanation of the agouti obesity syndrome.

Suggested Citation

  • Wei Fan & Bruce A. Boston & Robert A. Kesterson & Victor J. Hruby & Roger D. Cone, 1997. "Role of melanocortinergic neurons in feeding and the agouti obesity syndrome," Nature, Nature, vol. 385(6612), pages 165-168, January.
    • Handle: RePEc:nat:nature:v:385:y:1997:i:6612:d:10.1038_385165a0
    DOI: 10.1038/385165a0
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    Cited by:

    1. Carrie McMahon & James L Trevaskis & Christoph Carter & Kevin Holsapple & Kirsten White & Moupali Das & Sean Collins & Hal Martin & Leigh Ann Burns-Naas, 2020. "Lack of an association between clinical INSTI-related body weight gain and direct interference with MC4 receptor (MC4R), a key central regulator of body weight," PLOS ONE, Public Library of Science, vol. 15(2), pages 1-7, February.
    2. Hermanussen, M. & Tresguerres, J.A.F., 2005. "A new anti-obesity drug treatment: First clinical evidence that, antagonising glutamate-gated Ca2+ ion channels with memantine normalises binge-eating disorders," Economics & Human Biology, Elsevier, vol. 3(2), pages 329-337, July.
    3. Mingming Xing & Yang Li & Yuqi Zhang & Juemou Zhou & Danting Ma & Mengqi Zhang & Minglei Tang & Ting Ouyang & Fumiao Zhang & Xiaofeng Shi & Jianyuan Sun & Zuxin Chen & Weiping J. Zhang & Shuli Zhang &, 2024. "Paraventricular hypothalamic RUVBL2 neurons suppress appetite by enhancing excitatory synaptic transmission in distinct neurocircuits," Nature Communications, Nature, vol. 15(1), pages 1-21, December.
    4. Hongli Li & Yuanzhong Xu & Yanyan Jiang & Zhiying Jiang & Joshua Otiz-Guzman & Jessie C. Morrill & Jing Cai & Zhengmei Mao & Yong Xu & Benjamin R. Arenkiel & Cheng Huang & Qingchun Tong, 2023. "The melanocortin action is biased toward protection from weight loss in mice," Nature Communications, Nature, vol. 14(1), pages 1-16, December.

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