Gut regulation of bariatric surgery-induced bone loss

减肥手术引起的骨质流失的肠道调节（李振华，项目负责人）

Gut regulation of bariatric surgery-induced bone loss (Z. Li, Project Lead) Bariatric surgery-associated skeletal complications include a two-fold risk in bone fracture, a side effect that has been observed since the early 1990s. 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 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 contribution of the major surgical site (the stomach) has been largely neglected. We propose that gastric hormones contribute to bariatric surgery- induced skeletal complications. In key preliminary data, we found gastric X/A-like cells (P/D1 cells 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. The aims of this proposal 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 (in additional to ghrelin) derived from X/A-like cells that regulate bone marrow cells and 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, X/A-like cell derived ghrelin concentrations are decreased following VSG; therefore, we will test the protective effects of ghrelin on VSG-induced bone complications. For the second aim, we will determine the effects of X/A-like cell-derived secretome on adipogenesis, bone remodeling and hematopoiesis. Furthermore, unbiased transcriptomic and proteomic screens will be performed to define the secretome of X/A-like cells. This project will be supported by the Physiology Core for analyses of mouse body composition, activity, and energy expenditure. The Histopathology and Microscopy Core will provide services to characterize the tissue (gut and bone) phenotypes via histological and immunostaining analyses. The Proteomics and Lipidomics Core will perform protein profiling of the gastric X/A-like cell secretome. 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 bariatric surgery (Randy Seeley PhD), and bone homeostasis and remodeling (Clifford Rosen MD).