Gut regulation of bariatric surgery-induced bone loss

减肥手术所致骨丢失的肠道调节(李振国，项目负责人) 与减肥手术相关的骨骼并发症包括骨折风险的两倍，这种副作用 自20世纪90年代初以来一直被观察到。最常见的减肥手术是垂直袖状胃切除术 (VSG)，这会导致6-24个月后轴骨约3-7%的骨丢失。当前的临床管理 包括骨密度评估，摄入足够的膳食钙、维生素D和蛋白质， 和负重运动。这些对策最大限度地减少了继发性骨丢失，但不能完全预防。 去做减肥手术。更好地理解与减肥手术相关的骨丢失的机制是 有必要适当地设计和评估预防和治疗策略。胃肠激素的变化 和微生物区系是导致骨丢失的潜在机制，但主要手术部位( 胃)在很大程度上被忽视了。我们认为胃激素对减肥手术有贡献-- 导致骨骼并发症。在关键的初步数据中，我们发现了胃X/A样细胞(人类的P/D1细胞)， 一个独特的内分泌细胞群，有助于调节全球脂肪代谢，骨髓肥胖症 和骨骼的形成，暗示着胃骨轴。这项建议的目的是：1)确定 胃X/A样细胞源性分泌因子对血管紧张素转换酶诱导的骨丢失的影响 X/A样细胞分泌的调节骨髓的胃激素(除Ghrelin外)的特征 细胞和骨骼动态平衡。对于第一个目标，我们将利用白喉毒素模型来耗尽X/A样细胞 并分析骨骼参数以确定X/A样细胞在 骨骼动态平衡。此外，类X/A细胞衍生的Ghrelin浓度在VSG后降低； 因此，我们将测试Ghrelin对VSG诱导的骨并发症的保护作用。对于第二个 目的：探讨X/A样细胞源性分泌体在脂肪形成、骨改建和骨质疏松症中的作用。 造血术。此外，还将进行无偏见的转录和蛋白质组筛选，以确定 X/A样细胞的分泌体。该项目将由用于分析老鼠身体的生理学核心提供支持 成分、活动和能量消耗。组织病理学和显微镜核心将提供服务 通过组织学和免疫染色分析，确定组织(肠道和骨骼)的表型。这个 蛋白质组学和脂质组学核心公司将对胃X/A样细胞分泌组进行蛋白质图谱分析。这个 拟议的策略将严格测试胃X/A样细胞衍生的分泌因子的假设 导致血管紧张素转换酶相关骨骼并发症。确定这一细胞群体的重要性在 骨代谢将为控制减肥手术引起的骨丢失提供新的治疗靶点。这 该项目由一位新的初级研究员李子如博士领导，他将在 减肥手术(Randy Seeley PhD)和骨骼动态平衡与重建(Clifford Rosen MD)。

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).