Intact mTOR signaling in gastric X/A-like cells is required for bone homeostasis.

Introduction: Beyond its primary digestive functions, the stomach serves as an endocrine organ, secreting peptides that regulate appetite and energy balance. Among its enteroendocrine populations, X/A-like cells play a pivotal role in controlling food intake, glucose homeostasis, and lipid deposition. The secretion of X/A-like cell-derived hormones, including ghrelin and nesfatin-1, is regulated by the mechanistic target of rapamycin (mTOR) signaling pathway. However, the role of X/A-like cell mTOR signaling in skeletal metabolism remains unexplored. Method: Using previously validated and published mouse models with X/A-like cell-specific deletion of Results: Our findings demonstrate that mTOR signaling deficiency in X/A-like cells compromises bone health in male mice, evidenced by cortical bone loss at 12 weeks and trabecular bone reductions at 40 weeks. Furthermore, X/A-like cell-specific Discussion: Collectively, these findings identify a previously unrecognized role of gastric X/A-like cell mTOR signaling in the regulation of bone metabolism. Maintenance of intact mTOR signaling in these endocrine cells is necessary for bone homeostasis, revealing a novel gut-bone endocrine axis.