Gut regulation of bariatric surgery-induced bone loss

自20世纪90年代初以来，已观察到减肥手术相关的骨骼并发症，导致骨折风险增加高达两倍。最常见的减肥手术是垂直袖状胃切除术（VSG），6-24个月后会导致中轴骨骼约3-7%的骨丢失。目前的临床管理包括骨矿物质密度评估，摄入足够的膳食钙，维生素D和蛋白质，以及进行负重运动。这些对策最大限度地减少，但不能完全防止继发于减肥手术的骨丢失。更好地了解与减肥手术相关的骨丢失机制对于正确设计和评估预防和治疗策略是必要的。肠道激素和微生物群的变化是导致骨丢失的潜在机制，但主要手术部位（胃）的影响在很大程度上被忽视了。我们认为胃激素与减肥手术引起的骨骼并发症有关。在关键的初步数据中，我们发现胃X/A样细胞（人类P/D1细胞），一种独特的内分泌细胞群，有助于调节整体脂质代谢，骨髓肥胖和骨形成，这表明胃骨轴。我们的目标是：1）确定胃X/A样细胞衍生的分泌因子对VSG诱导的骨丢失的影响; 2）鉴定和表征来自调节骨骼稳态的X/A样细胞的胃激素。对于第一个目标，我们将利用白喉毒素模型来消耗成年小鼠胃中的X/A样细胞，并分析骨参数以确定X/A样细胞在骨稳态中的重要性。此外，我们将激活X/A样细胞中的mTOR信号传导，以测试对VSG诱导的骨丢失的保护作用。对于第二个目标，我们将验证ghrelin对VSG诱导的骨并发症的保护作用，并确定X/A样细胞来源的分泌体对脂肪生成、骨生成和破骨细胞生成的影响。此外，将进行无偏转录组学和蛋白质组学筛选以确定X/A样细胞的分泌因子。该项目将得到生理学核心的支持，用于分析小鼠的身体组成、活动和能量消耗。此外，组织学和显微镜核心以及蛋白质组学和脂质组学核心将分别协助评估组织（肠道和骨骼）表型和蛋白质谱，以确定分子特征。所提出的策略将严格测试的假设，胃X/A样细胞衍生的分泌因子有助于VSG相关的骨骼并发症。确定该细胞群在骨代谢中的重要性将为管理减肥手术引起的骨丢失提供新的治疗靶点。该项目由新的初级研究员Ziru Li博士领导，他将得到减肥手术（Randy塞利博士）和骨稳态和重塑（Clifford罗森医学博士）领域的杰出专家导师的支持。

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 homeostasis and remodeling (Clifford Rosen MD) fields.