biostudies-literatureKubrak ONatur og Univers, Det Frie Forskningsråd (Natural Sciences, Danish Council for Independent Research)Novo Nordisk Fonden (Novo Nordisk Foundation)Natur og Univers, Det Frie ForskningsrådNovo Nordisk Fonden6126https://www.ebi.ac.uk/biostudies/studies/S-EPMC11271308biostudies-literatureUnknown15(1)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 secretiNature communicationsLGR signaling mediates muscle-adipose tissue crosstalk and protects against diet-induced insulin resistance.PMC112713088021-00055BNNF21OC0070402NNF22OC0078344Mazzoni GKoyama THansen JLHalberg KVHansen JBTexada MJLarsen MRJorgensen AFMadsen DRewitz KKubrak ONagy SLassen MHald JfalseLGR signaling mediates muscle-adipose tissue crosstalk and protects against diet-induced insulin resistance.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 secreti2024-01-01T00:00:00Z2024 Jul2026-07-15T04:18:06.17Z2025-04-19T13:12:27.39ZS-EPMC112713083903313910.1038/s41467-024-50468-w