Effects of High Fat Diet and Environmental Obesogen Co-Exposure on Osteoporosis

描述（由申请人提供）：骨质疏松症是老龄化人口的主要公共健康威胁。骨质疏松症被比作“骨的肥胖”，因为正常的骨量被脂肪组织取代而丢失。骨质疏松症的一个公认的危险因素是绝经妇女雌激素分泌的下降。一个新发现的危险因素是高脂肪饮食和肥胖。这种骨骼健康危机的一个未被充分认识的方面是暴露于环境致肥因子的贡献，这些污染物破坏了脂肪生成和能量平衡的稳态控制。越来越多的环境污染物，包括有机素和邻苯二甲酸盐，被认为具有激活过氧化物酶体增殖物激活受体（PPAR）的能力，PPAR是脂肪细胞分化的主要调节剂。激活PPAR？骨质疏松与脂肪生成增加和骨生成减少有关。自从PPAR吗?在控制多能骨髓干细胞（MSC）分化的调控网络的顶端，假设环境致肥因子是骨髓毒物。目前尚不清楚的是，暴露于高脂肪饮食和环境致肥因子是如何共同改变骨稳态的。长期目标是确定环境污染物如何激活骨髓中的核受体来改变间充质干细胞分化，以及扭曲的间充质干细胞分化如何影响骨髓功能。本研究的目的是研究高脂肪饮食和环境致肥因子是如何共同影响成骨的。假设1)环境致肥源通过激活PPAR诱导脂肪生成并抑制骨生成。RXR是指导间质干细胞在成骨和成脂谱系之间分化的调节控制的中心点，2)共同暴露于饮食脂肪酸促进脂肪形成，3)暴露于高脂肪饮食将与环境致肥因子协同作用，加速体内骨质疏松的进展。通过追求以下两个特定目标，这些假设将得到验证：1)确定脂肪酸和肥胖原暴露的功能相互作用及其对控制MSC分化机制的影响。在原代间充质干细胞培养中，由邻苯二甲酸盐、有机锡和膳食脂肪酸诱导的控制成脂和成骨分化平衡的中枢转录机制的改变，以及共同暴露的定性/定量影响将被描述。2)在体内研究高脂肪饮食对肥胖所致骨质疏松的影响。本研究将研究低剂量三丁基锡（TBT）和不同脂肪含量饮食对C57BL/6雌性小鼠骨骼结构、质量、脂肪生成、成骨和破骨细胞活性介质表达的影响。鉴于日益增长的老龄化人口已经面临骨质疏松症的发展风险，迫切需要确定驱动饮食和污染物驱动的骨生成抑制的分子机制，以便开发适当的方法来预防疾病的发生/进展。

DESCRIPTION (provided by applicant): Osteoporosis is the primary public health threat for the aging population. Osteoporosis has been likened to "obesity of the bone" because normal bone mass is lost as it is replaced with adipose tissue. A well recognized risk factor for development of osteoporosis is the decline of estrogen secretion in women at menopause. A newly recognized risk factor is a high fat diet and obesity. An underappreciated aspect of this bone health crisis is the contribution of exposure to environmental obesogens, contaminants that disrupt the homeostatic controls of adipogenesis and energy balance. A growing number of environmental contaminants, including organotins and phthalates, are being recognized for their ability to activate peroxisome proliferator activated receptor gamma (PPAR?), the master regulator of adipocyte differentiation. Activation of PPAR? in bone is associated with increased adipogenesis and decreased osteogenesis. Since PPAR? is poised at the apex of a regulatory network that controls multi-potent marrow stem cell (MSC) differentiation, it is posited that environmental obesogens are bone marrow toxicants. What is unclear is how exposure to both a high fat diet and environmental obesogens cooperate to modify bone homeostasis. The long term goal is to determine how activation of nuclear receptors in the bone marrow by environmental contaminants modifies MSC differentiation and how skewed MSC differentiation impacts bone marrow function. The objective of this proposal is to examine how exposure to a high fat diet and environmental obesogens cooperate to impair osteogenesis. It is hypothesized 1) that environmental obesogens induce adipogenesis and suppress osteogenesis through activation of PPAR? and RXR, which is a central point of regulatory control in directing MSC differentiation between osteogenic and adipogenic lineages, 2) that co-exposure to dietary fatty acids facilitates adipogenesis and 3) that exposure to a high fat diet will synergize with environmental obesogens to accelerate the progression of osteo- porosis in vivo. By pursuing the following two Specific Aims these hypotheses will be tested: 1) Determine the functional interactions of fatty acid and obesogen exposure and their effects on the mechanisms that control MSC differentiation. Alterations in central transcriptional mechanisms that control the balance between adipogenic and osteogenic differentiation that are induced by a phthalate, an organotin, and dietary fatty acids in primary MSC cultures and define the qualitative/quantitative effects of co-exposure will be delineated. 2) Examine the effect of a high fat diet on obesogen-induced osteoporosis in vivo. The effect of low dose tributyltin (TBT) exposure and diets differing in fat content in intact and ovariectomized female C57BL/6 mice on bone structure, quality and expression of mediators of adipogenesis, osteogenesis and osteoclast activity will be investigated. Given the growing aging population that is already at risk for development of osteoporosis, it is urgent that the molecular mechanisms driving diet- and contaminant-driven suppression of osteogenesis be identified so that appropriate approaches can be developed to prevent the onset/progression of disease.