Abstract
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 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. 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 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. 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.