SUN-671 The Gut-Bone Axis: The Role of X/A-like Cells in Skeletal Regulation

Abstract Disclosure: C.D. Picoli: None. J.R. Aponte: None. T. Feng: None. P. Le: None. C.J. Rosen: None. Z. Li: None. Background: Bariatric surgery is the most effective treatment for severe obesity and type 2 diabetes but comes with side effects, including bone loss and elevated fracture risks overtime. While changes in gut hormones and the microbiota have been studied, the role of the stomach, the primary surgical site, remains underexplored. X/A-like cells, which account ∼20% of endocrine cells in the stomach, are major source of circulating ghrelin. Vertical sleeve gastrectomy (VSG), the most common bariatric procedure, reduces ghrelin levels in humans and rodents. We sought to investigate how X/A-like cell-derived factors contribute to bone loss following VSG. Methods: Male C57BL/6J mice were fed a high-fat diet (HFD) for 8 weeks before VSG. A subset of these mice received ghrelin supplementation post-surgery. Changes in fat mass, glucose metabolism, and skeletal parameters were determined 4 weeks after surgery. Additionally, we depleted X/A-like cells by breeding ghrelin (Ghrl)-Cre mice with diphtheria toxin receptor (DTR) mice, which were treated with diphtheria toxin (DT) at 12 weeks of age. Metabolic and bone parameters under chow and HFD conditions were measured 4 weeks after DT treatment. Results: VSG led to a marked reduction in fat mass and improvement in glucose metabolism; however, it also induced both trabecular and cortical bone loss. Supplementation with exogenous active ghrelin did not influence these outcomes, indicating that ghrelin may not be the primary endocrine factor driving the metabolic benefits and skeletal complications following VSG. However, our in vitro data suggested that secretory factors from gastric mucosa explants promote osteogenesis while inhibit osteoclastogenesis. Additionally, we observed a significant loss of X/A-like cells following VSG. To further investigate the role of X/A-like cells in whole-body and bone metabolism, we treated Ghrl-DTR mice with DT, which resulted in an ∼93% reduction in X/A-like cell numbers. This cell depletion was associated with improved glucose metabolism and impaired bone homeostasis under chow conditions. Similarly, X/A-like cell depletion tended to improve glucose metabolism, significantly decreased trabecular and cortical bone, and increased bone turnover markers. The similarity between the effects of X/A-like cell depletion and those observed with VSG strongly suggests that these cells play a pivotal role in mediating VSG-induced changes in glucose metabolism and skeletal health. Conclusions: Our VSG mouse model successfully mirrored the metabolic improvements and skeletal complications reported in clinical patients. Notably, ghrelin was not identified as a major contributor to the glucose improvements or skeletal issues induced by VSG. Instead, our findings underscore the critical role of X/A-like cells in maintaining skeletal homeostasis, potentially through the secretion of as-yet unidentified factors. Presentation: Sunday, July 13, 2025