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LGR signaling mediates muscle-adipose tissue crosstalk and protects against diet-induced insulin resistance

Author

Listed:
  • Olga Kubrak

    (University of Copenhagen)

  • Anne F. Jørgensen

    (University of Copenhagen
    Novo Nordisk Park)

  • Takashi Koyama

    (University of Copenhagen)

  • Mette Lassen

    (University of Copenhagen)

  • Stanislav Nagy

    (University of Copenhagen)

  • Jacob Hald

    (Novo Nordisk Park)

  • Gianluca Mazzoni

    (Novo Nordisk Park)

  • Dennis Madsen

    (Novo Nordisk Park)

  • Jacob B. Hansen

    (University of Copenhagen)

  • Martin Røssel Larsen

    (University of Southern Denmark)

  • Michael J. Texada

    (University of Copenhagen)

  • Jakob L. Hansen

    (Novo Nordisk Park)

  • Kenneth V. Halberg

    (University of Copenhagen)

  • Kim Rewitz

    (University of Copenhagen)

Abstract

Obesity impairs tissue insulin sensitivity and signaling, promoting type-2 diabetes. Although improving insulin signaling is key to reversing diabetes, the multi-organ mechanisms regulating this process are poorly defined. Here, we screen the secretome and receptome in Drosophila to identify the hormonal crosstalk affecting diet-induced insulin resistance and obesity. We discover a complex interplay between muscle, neuronal, and adipose tissues, mediated by Bone Morphogenetic Protein (BMP) signaling and the hormone Bursicon, that enhances insulin signaling and sugar tolerance. Muscle-derived BMP signaling, induced by sugar, governs neuronal Bursicon signaling. Bursicon, through its receptor Rickets, a Leucine-rich-repeat-containing G-protein coupled receptor (LGR), improves insulin secretion and insulin sensitivity in adipose tissue, mitigating hyperglycemia. In mouse adipocytes, loss of the Rickets ortholog LGR4 blunts insulin responses, showing an essential role of LGR4 in adipocyte insulin sensitivity. Our findings reveal a muscle-neuronal-fat-tissue axis driving metabolic adaptation to high-sugar conditions, identifying LGR4 as a critical mediator in this regulatory network.

Suggested Citation

  • Olga Kubrak & Anne F. Jørgensen & Takashi Koyama & Mette Lassen & Stanislav Nagy & Jacob Hald & Gianluca Mazzoni & Dennis Madsen & Jacob B. Hansen & Martin Røssel Larsen & Michael J. Texada & Jakob L., 2024. "LGR signaling mediates muscle-adipose tissue crosstalk and protects against diet-induced insulin resistance," Nature Communications, Nature, vol. 15(1), pages 1-22, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-50468-w
    DOI: 10.1038/s41467-024-50468-w
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    References listed on IDEAS

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