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

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. Hansen, Kenneth V. Halberg and Kim Rewitz ()
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Olga Kubrak: University of Copenhagen
Anne F. Jørgensen: University of Copenhagen
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

Nature Communications, 2024, vol. 15, issue 1, 1-22

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-50468-w

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