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

• 批准号: 8258164
• 负责人: Jennifer J Schlezinger
• 金额: $ 24.56万
• 依托单位: BOSTON UNIVERSITY MEDICAL CAMPUS
• 依托单位国家: 美国
• 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/8258164
• 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; osteogenic; phthalates; prevent; programs; rosiglitazone; small hairpin RNA; stem cell differentiation; toxicant; tributyltin

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. PUBLIC HEALTH RELEVANCE: Osteoporosis is the primary public health threat for the aging population, particularly for post-menopausal women. Exposures to a high fat diet and environmental obesogens, specifically contaminants that activate the master regulator of fat formation, are underappreciated contributors to the risk of developing osteoporosis. Studies in this proposal are designed to define the molecular mechanisms by which phthalates and organotins cause fat formation in bone marrow and suppress bone formation and to define how these processes are exacerbated by consumption of a high fat diet.

描述(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“骨肥胖症”，因为正常的骨量会被脂肪组织取代而丢失。绝经期妇女雌激素分泌下降是导致骨质疏松症的一个公认的危险因素。一个新发现的危险因素是高脂肪饮食和肥胖。这场骨骼健康危机被低估的一个方面是暴露于环境致肥者的贡献，环境致肥者是破坏脂肪生成和能量平衡的动态平衡控制的污染物。越来越多的环境污染物，包括有机锡和邻苯二甲酸酯，被认为具有激活PPAR？的能力，PPAR？是脂肪细胞分化的主要调节因子。激活PPAR？在骨骼中，脂肪生成增加，成骨减少。从PPAR开始？处于控制多潜能骨髓干细胞(MSC)分化的调控网络的顶端，因此假设环境致病物质是骨髓毒物。目前尚不清楚的是，暴露在高脂肪饮食和环境致肥者的环境中如何合作来改变骨骼稳态。长期目标是确定环境污染物激活骨髓中的核受体如何改变MSC分化，以及扭曲的MSC分化如何影响骨髓功能。这项建议的目的是研究暴露于高脂肪饮食和环境致肥菌是如何协同作用来损害成骨的。假设1)环境致肥者通过激活PPAR诱导脂肪生成和抑制成骨。和RXR，它是指导成骨和成脂MSC分化的调控中心点，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者协同作用，加速体内骨质疏松症的进展。通过追求以下两个特定目标，这些假说将被检验：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分化的机制的影响。在原代MSC培养中，控制由邻苯二甲酸盐、有机锡和膳食脂肪酸诱导的成脂和成骨分化之间的平衡的中央转录机制的变化将被描绘出来，并确定共同暴露的质量/数量影响。2)体内观察高脂饮食对肥胖大鼠骨质疏松的影响。研究低剂量三丁基锡(TBT)暴露和不同脂肪含量的饲料对去卵巢和正常雌性C57BL/6小鼠骨骼结构、质量以及成脂、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发展成骨质疏松症的风险，迫切需要确定驱动饮食和污染物驱动的成骨抑制的分子机制，以便能够开发适当的方法来预防疾病的发生/发展。 公共卫生相关性：骨质疏松症是老龄化人口，特别是绝经后妇女的主要公共健康威胁。暴露于高脂肪饮食和环境致肥者，特别是激活脂肪形成的主要调节器的污染物，是导致骨质疏松症风险的被低估的因素。这项建议中的研究旨在确定邻苯二甲酸盐和有机锡导致骨髓中脂肪形成和抑制骨形成的分子机制，并确定高脂肪饮食是如何加剧这些过程的。