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

高脂肪饮食和环境致肥胖因素共同暴露对骨质疏松症的影响

基本信息

批准号：
8538387
负责人：
Jennifer J Schlezinger
金额：
$ 24.06万
依托单位：
BOSTON UNIVERSITY MEDICAL CAMPUS
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-09-01 至 2014-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8538387
关键词：
2,4-thiazolidinedione Adipose tissue Age Aging American Anabolism Automobile Driving Bone Marrow C57BL/6 Mouse Catabolism Cell Culture Techniques Chemicals Consumption Defect Development Diet Dietary Fatty Acid Disease Progression Dose Environmental Pollution Equilibrium Estrogens Exposure to Fatty Acids Fatty acid glycerol esters Female Fracture Goals Health Care Costs Healthcare Hematopoiesis Homeostasis In Vitro Ligands Marrow Mediator of activation protein Menopause Modeling Molecular Mono-S Myelopoiesis Nuclear Receptors Obesity Organ Osteoclasts Osteogenesis Osteopenia Osteoporosis PPAR gamma Palmitic Acids Pathway interactions Peroxisome Proliferator-Activated Receptors Population Postmenopause Process Public Health RXR Research Risk Risk Factors Stem cells Structure Technology Testing Therapeutic Thiazolidinediones United States Unsaturated Fatty Acids Vulnerable Populations Woman Xenobiotics adipocyte differentiation aging population bone bone health bone loss bone mass defined contribution design energy balance in vivo lipid biosynthesis mono-(2-ethylhexyl)phthalate obesogen osteogenic phthalates prevent programs rosiglitazone small hairpin RNA stem cell differentiation toxicant tributyltin

项目摘要

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.

描述（由申请人提供）：骨质疏松症是老年人群的主要公共卫生威胁。骨质疏松症被比作“骨的肥胖”，因为正常的骨量丢失，因为它被脂肪组织取代。骨质疏松症的一个公认的危险因素是绝经期妇女雌激素分泌的下降。一个新认识到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胖剂的贡献，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，包括有机锡和邻苯二甲酸盐，被认为具有激活过氧化物酶体增殖物激活受体γ（PPAR？）的能力，脂肪细胞分化的主要调节因子。激活PPAR？与脂肪生成增加和骨生成减少有关。自从PPAR？处于控制多能骨髓干细胞（MSC）分化的调节网络的顶点，假定环境致肥剂是骨髓毒物。目前尚不清楚的是，高脂肪饮食和环境致肥剂如何共同改变骨稳态。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MSC分化，以及MSC分化的倾斜如何影响骨髓功能。这个建议的目的是研究暴露于高脂肪饮食和环境致肥剂如何合作损害骨生成。假设1）环境致胖剂通过激活PPAR？和RXR，其是指导MSC在成骨和成脂谱系之间分化的调节控制的中心点，2）共暴露于膳食脂肪酸促进脂肪生成，和3）暴露于高脂肪饮食将与环境致胖剂协同作用以加速体内骨质疏松症的进展。通过追求以下两个具体目标，将测试这些假设：1）确定脂肪酸和肥胖素暴露的功能相互作用及其对控制MSC分化机制的影响。改变中央转录机制，控制成脂和成骨分化之间的平衡，诱导邻苯二甲酸酯，有机锡，和膳食脂肪酸在原代MSC培养，并定义定性/定量的影响共同曝光将被描绘。2)检查高脂饮食对体内肥胖素诱导的骨质疏松症的影响。将研究低剂量三丁基锡（TBT）暴露和不同脂肪含量的饮食对完整和卵巢切除雌性C57 BL/6小鼠骨结构、质量和脂肪生成、骨生成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处于骨质疏松症发展的风险中，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，以便可以开发适当的方法来预防疾病的发作/进展。