SAT-688 - Gastric Hormones Ghrelin and Somatostatin Increase Physical Activity after Vertical Sleeve Gastrectomy without Preventing Bone Loss

Background: Even in the era of pharmacological weight-loss therapies, bariatric surgeries remain the most effective and durable treatment for severe obesity and type 2 diabetes. However, the side effects include bone loss and increased fracture risk. Our previous studies showed that vertical sleeve gastrectomy (VSG), the most performed bariatric surgery, reduces circulating ghrelin levels and ghrelin-producing X/A-like cells. Genetic ablation of X/A-like cells recapitulates the bone loss phenotype observed after VSG. Importantly, physiological-level ghrelin supplementation fails to prevent VSG-induced bone loss, suggesting that additional, unidentified X/A-like cell–derived hormones contribute to skeletal complications after VSG.

Methods: To identify additional X/A-like cell–derived hormones altered by VSG, we performed untargeted proteomics on gastric mucosa from X/A-like cell–depleted and VSG mice and validated hormonal gene expression using snRNA-seq. Somatostatin (Sst) emerged as a second leading candidate alongside ghrelin (Ghrl). Obese male C57BL/6J mice underwent sham or VSG and received saline or combined Ghrl/Sst supplementation via osmotic minipumps for 4 weeks. Changes in body composition, glucose metabolism, energy expenditure (EE), physical activity and skeletal parameters were determined between 3–4 weeks after surgery.

Results: Proteomic analyses revealed that X/A-like cell ablation reduced gastric ghrelin by >90% and unexpectedly decreased somatostatin by ~70%. We further demonstrated for the first time that X/A-like cells partially overlapped with Sst-expressing cells. Both Ghrl and Sst proteins were significantly reduced in gastric mucosa following VSG, which was corroborated by snRNA-seq showing marked depletion of both Ghrl⁺ X/A-like cells and Sst⁺ D cells. Combined Ghrl/Sst supplementation did not alter VSG-induced changes in body weight, fat mass, glucose metabolism, or food intake but reduced water intake. Ghrl/Sst supplementation increased EE, oxygen consumption, and carbon dioxide production during the dark phase in both sham and VSG mice. Notably, Ghrl/Sst supplementation selectively increased ambulatory activity, running time, and wheel distance and reduced sleep time in VSG mice. Despite these metabolic and behavioral effects, Ghrl/Sst supplementation did not prevent VSG-induced bone loss.

Conclusions: X/A-like cells produce a broader endocrine repertoire than previously appreciated, including substantial Sst expression. The overlap between X/A-like cells and D cells reveals a previously unrecognized gastric endocrine subpopulation. Although Ghrl and Sst together enhance physical activity after VSG, they are insufficient to protect against post-surgical bone loss, indicating that additional X/A-like cell–derived factors may contribute to skeletal deterioration following VSG.

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