The GLP-1 analog, exendin-4, improves bone material properties and strength through a central relay in ovariectomized mice

Glucagon-like peptide-1 (GLP-1) has previously been shown to be indispensable for optimal bone strength by acting at the bone material level. However, it was not fully clear whether the effects of GLP-1 were mediated by direct or indirect actions on bone cells. In the present study, we were unable to demonstrate the expression of the GLP-1 receptor (GLP-1r) in bone tissue at the gene expression level using qPCR and in situ hybridization, or at the protein level. Furthermore, the peripheral administration of exendin-4, a specific GLP-1r agonist, in ovariectomized BALB/c mice enhanced postyield displacement (18%) and energy-to-fracture (24%), as well as bone volume/total volume (BV/TV) (11%), trabecular number (Tb.N) (6%), and collagen maturity (18%). These bone effects were still observed when exendin-4 was centrally administered into the lateral cerebral ventricle. On the contrary, the peripheral administration of exendin-4 coupled to bovine serum albumin, a GLP-1r agonist that cannot penetrate the brain, failed to replicate the positive effects on bone despite increased calcitonin secretion. Altogether, these data confirm that GLP-1r agonists represent an interesting approach for managing bone fragility due to ovariectomy but also suggest that GLP-1r agonists require a central relay-yet to be identified-to exert positive effects on bone physiology. Further studies are needed to decipher the mechanisms of action of GLP-1 and GLP-1r agonists on bone physiology.<b>NEW & NOTEWORTHY</b> This study discovered that medications mimicking GLP-1, like exendin-4, improve bone strength and structure in mice, including better bone volume and collagen quality. Interestingly, exendin-4's effects were observed when delivered to the brain but not when prevented from reaching it. This suggests GLP-1 influences bones through brain signals rather than acting directly on bone. Although GLP-1 treatments show promise for preventing bone weakness, more research is needed to understand this brain-bone connection.