Gastric Endocrine Functions in Skeletal Homeostasis - Bariatric surgery-associated skeletal complications have been observed since the early 1990s, and are associated with increased fracture risk. The most prevalent bariatric surgery is vertical sleeve gastrectomy (VSG), which removes most of the stomach. By 12 months after surgery, bone loss of 4–8% in the hip and 3– 10% in the femoral neck increases fracture risk 1.3 to 2.3-fold. 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 clearer mechanistic understanding of bone loss associated with bariatric surgery is necessary to properly design preventive strategies. Changes in gut hormones and microbiota have been proposed to drive bone loss, but the effects of loss of the stomach have been largely neglected. We propose that gastric secretory factors contribute to bariatric surgery-induced skeletal complications. In key preliminary data, we found a loss of gastric X/A-like cells (P/D1 cell in humans) and a decrease in secreted ghrelin following VSG. Genetic ablation of X/A-like cells was found to improve glucose metabolism and impair trabecular bone mass, which mimics the metabolic and skeletal consequences of VSG. However, ghrelin supplementation alone does not prevent VSG-induced bone loss. Our proteomic profiling identified ghrelin and somatostatin as the top two secretory proteins enriched in X/A-like cells and decreased by VSG. Moreover, circulating exosome concentrations and gastric RAB27A, a Rab GTPase critical for extracellular vesicle (EV) secretion, were significantly upregulated by VSG. These data suggest that X/A-like cells are a source of secretory factors vital to bone homeostasis, and bariatric surgery disrupts this balance. The specific aims of this proposal are: 1) to define the skeletal and metabolic consequences of gastric X/A-like cell ablation and identify X/A-like cell- derived secretory factors that affect skeletal homeostasis; and 2) to determine the effects of gastric X/A-like cell-derived hormonal factors and EV cargoes on VSG-induced bone loss. In aim 1, we will utilize the X/A-like cell ablation mouse model to determine the importance of these cells in skeletal health under conditions of metabolic stress, including diet-induced obesity and estrogen deficiency. Furthermore, we will identify secretory factors from X/A-like cells and determine their roles in osteoblast, osteoclast and adipocyte differentiation and function. In aim 2, we will test whether somatostatin can enhance the pro-osteogenic effects of ghrelin and protect against VSG-induced bone complications. In addition, we will delete Rab27a in X/A-like cells to determine its pathophysiological functions in bone, glucose and lipid metabolism under lean healthy, obese and VSG conditions. Understanding the significance of X/A-like cells in bone metabolism holds promise for developing new therapeutic targets to manage bariatric surgery-induced bone loss, which remains one of the few time-tested options for improving health of severely obese individuals.
