Bariatric surgery-associated skeletal complications have been observed since the early 1990s, leading to up to a two-fold increase in fracture risk. The most common bariatric surgery is vertical sleeve gastrectomy (VSG), which leads to ~3-7% bone loss at the axial skeleton after 6-24 months. Current clinical management includes bone mineral density assessments, consumption of adequate dietary calcium, vitamin D, and protein, and performance of weight-bearing exercise. These countermeasures minimize, but do not fully prevent bone loss secondary to bariatric surgery. A better mechanistic understanding of bone loss associated with bariatric surgery is necessary to properly design and evaluate preventive and therapeutic strategies. Changes in gut hormones and microbiota are potential mechanisms driving bone loss, but the effects of the major surgical site (the stomach) have been largely neglected. We propose that gastric hormones contribute to bariatric surgeryinduced skeletal complications. In key preliminary data, we found that gastric X/A-like cells (P/D1 cell in humans), a unique endocrine cell population, contribute to the regulation of global lipid metabolism, marrow adiposity and bone formation, suggesting a stomach bone axis. Our aims are: 1) to determine the effects of gastric X/A-like cell-derived secretory factors on VSG-induced bone loss and 2) to identify and characterize gastric hormones from X/A-like cells that regulate skeletal homeostasis. For the first aim, we will utilize a diphtheria toxin model to deplete X/A-like cells in the adult mouse stomach, and analyze bone parameters to determine the importance of X/A-like cells in bone homeostasis. In addition, we will activate mTOR signaling in X/A-like cells to test for protection against VSG-induced bone loss. For the second aim, we will validate the protective effects of ghrelin on VSG-induced bone complications, and determine the effects of the X/A-like cellderived secretome on adipogenesis, osteogenesis and osteoclastogenesis. Furthermore, unbiased transcriptomic and proteomic screens will be performed to define the secretory factors of X/A-like cells. This project will be supported by the Physiology Core for analyses of mouse body composition, activity, and energy expenditure. In addition, the Histopathology and Microscopy Core and the Proteomics and Lipidomics Core will assist in assessment of tissue (gut and bone) phenotypes and protein profiling to define molecular signatures, respectively. The proposed strategy will rigorously test the hypothesis that gastric X/A-like cell-derived secretory factors contribute to VSG-associated skeletal complications. Determination of the importance of this cell population in bone metabolism will provide new therapeutic targets for managing bariatric surgery-induced bone loss. This project is led by a new junior investigator, Dr. Ziru Li, who will be supported by outstanding expert mentors in the bariatric surgery (Randy Seeley PhD), and bone h...