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A homeostatic gut-to-brain insulin antagonist restrains neuronally stimulated fat loss

Author

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  • Chung-Chih Liu

    (The Scripps Research Institute
    The Scripps Research Institute)

  • Ayub Khan

    (The Scripps Research Institute)

  • Nicolas Seban

    (The Scripps Research Institute)

  • Nicole Littlejohn

    (The Scripps Research Institute)

  • Aayushi Shah

    (The Scripps Research Institute)

  • Supriya Srinivasan

    (The Scripps Research Institute)

Abstract

In C. elegans mechanisms by which peripheral organs relay internal state information to the nervous system remain unknown, although strong evidence suggests that such signals do exist. Here we report the discovery of a peptide of the ancestral insulin superfamily called INS-7 that functions as an enteroendocrine peptide and is secreted from specialized cells of the intestine. INS-7 secretion is stimulated by food withdrawal, increases during fasting and acts as a bona fide gut-to-brain peptide that attenuates the release of a neuropeptide that drives fat loss in the periphery. Thus, INS-7 functions as a homeostatic signal from the intestine that gates the neuronal drive to stimulate fat loss during food shortage. Mechanistically, INS-7 functions as an antagonist at the canonical DAF-2 receptor and functions via FOXO and AMPK signaling in ASI neurons. Phylogenetic analysis suggests that INS-7 bears greater resemblance to members of the broad insulin/relaxin superfamily than to conventional mammalian insulin and IGF peptides. The discovery of an endogenous insulin antagonist secreted by specialized intestinal cells with enteroendocrine functions suggests unexpected and important properties of the intestine and its role in directing neuronal functions.

Suggested Citation

  • Chung-Chih Liu & Ayub Khan & Nicolas Seban & Nicole Littlejohn & Aayushi Shah & Supriya Srinivasan, 2024. "A homeostatic gut-to-brain insulin antagonist restrains neuronally stimulated fat loss," Nature Communications, Nature, vol. 15(1), pages 1-16, December.
  • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-51077-3
    DOI: 10.1038/s41467-024-51077-3
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    References listed on IDEAS

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    1. Lavinia Palamiuc & Tallie Noble & Emily Witham & Harkaranveer Ratanpal & Megan Vaughan & Supriya Srinivasan, 2017. "A tachykinin-like neuroendocrine signalling axis couples central serotonin action and nutrient sensing with peripheral lipid metabolism," Nature Communications, Nature, vol. 8(1), pages 1-14, April.
    2. Rachel L. Batterham & Michael A. Cowley & Caroline J. Small & Herbert Herzog & Mark A. Cohen & Catherine L. Dakin & Alison M. Wren & Audrey E. Brynes & Malcolm J. Low & Mohammad A. Ghatei & Roger D. C, 2002. "Gut hormone PYY3-36 physiologically inhibits food intake," Nature, Nature, vol. 418(6898), pages 650-654, August.
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