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

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. Using previously validated and published mouse models with X/A-like cell-specific deletion of Mtor or its upstream inhibitor Tsc1, we assessed bone phenotypes at 12 and 40 weeks of age under chow-fed conditions. Skeletal effects were also evaluated under pathological bone loss conditions, including estrogen deficiency (ovariectomy) and caloric restriction. 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 Mtor deletion significantly exacerbated bone loss in female mice following ovariectomy, impacting both trabecular and cortical parameters. In contrast, activation of mTOR signaling via Tsc1 deletion in X/A-like cells did not alter bone mass under either chow ad libitum or calorie-restricted conditions. 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.