Environmental Endocrine Disruptors and Adipocyte Biology

环境内分泌干扰物和脂肪细胞生物学

• 批准号: 7674978
• 负责人: Robert M Sargis
• 金额: $ 5.34万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-01 至 2010-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7674978
• 关键词: Adipocytes; Adipose tissue; Affect; Attention; Behavior; Binding; Biochemical; Biological Assay; Cell Differentiation Induction; Cellular biology; Chemical Exposure; Chemicals; Clinical; Data; Development; Diabetes Mellitus; Dose; Dyslipidemias; Endocrine; Endocrine Disruptors; Endocrine Glands; Endocrine disruption; Environmental Pollutants; Environmental Pollution; Epidemic; Epidemiology; Estrogen Nuclear Receptor; Explosion; Exposure to; Foundations; Gene Proteins; Glucocorticoid Receptor; Glucose; Goals; Gonadal Steroid Hormones; Homeostasis; Human; Insulin; Insulin Resistance; Lead; Ligands; Lipids; Lipolysis; Luciferases; Measurement; Mediating; Metabolic; Molecular; Non-Insulin-Dependent Diabetes Mellitus; Nuclear; Nuclear Hormone Receptors; Obesity; Pathway interactions; Peroxisome Proliferators; Phosphotransferases; Physiological; Physiology; Play; Population; Prevalence; Process; Production; Public Health; Regulation; Reporter; Rodent; Role; Sexual Development; Signal Transduction; Staging; Testing; Work; adipocyte biology; adipocyte differentiation; bioaccumulation; chemical binding; glucose uptake; human data; insight; insulin sensitivity; insulin signaling; lipid biosynthesis; lipid metabolism; marine organism; member; novel; pollutant; protein expression; public health relevance; reproductive axis; research study; transcription factor

DESCRIPTION (provided by applicant): Rates of obesity and diabetes are reaching epidemic proportions, yet the mechanisms underlying their rapid expansion are incompletely understood. Data showing a correlation between synthetic chemical production and obesity rates has prompted some to propose the "environmental obesogen hypothesis" that suggests a potential causative role for some environmental pollutants in the development of obesity. While some endocrine disrupting chemicals have been shown to promote the differentiation of adipocytes, the exact pathways leading to this phenomenon are incompletely characterized. Previous work studying the impact of endocrine disrupters on the reproductive axis has demonstrated that agents can directly bind to and regulate the nuclear estrogen receptor. Since adipocytes are highly regulated by a number of transcription factors, we will test the hypothesis that endocrine disrupting chemicals impact adipocyte function via direct modulation of nuclear transcription factors and changes in gene/protein expression. Thus, the overarching goal of this application is to define the specific molecular mechanisms by which endocrine disrupting chemicals affect preadipocyte differentiation and mature adipocyte energy homeostasis. A specific focus of this work will be to differentiate the physiological effects of endocrine disruptors mediated through the glucocorticoid receptor as compared to the peroxisome proliferator activator-y, as these two pathways have antagonistic effects on insulin sensitivity in the mature adipocyte. Specific Aim 1 will identify endocrine disruptors that alter the activity of specific nuclear transcription factors in the preadipocyte and determine their effects on differentiation of 3T3-L1 preadipocytes. Particular attention will also be given to potential synergy among endocrine disruptors acting through different pathways that may explain how exposure to low doses of multiple chemicals may result in inappropriate preadipocyte differentiation. Specific Aim 2 will characterize the effects of endocrine disruptors on insulin-mediated energy homeostasis in the mature adipocyte, including activation of insulin signaling cascades and regulation of glucose uptake, lipogenesis, and anti-lipolysis. A special focus of this aim will be to determine whether exposure to endocrine disruptors during specific developmental windows changes the insulin sensitivity of the mature adipocyte. PUBLIC HEALTH RELEVANCE: This work will help characterize the means by which environmental pollutants affect the development and behavior of fat cells in order to understand how synthetic chemicals may contribute to the obesity epidemic; these studies could also provide novel insights into the mechanisms underlying altered fat cell biology in obesity. Finally, these studies could support public health efforts to remediate environmental contamination.

描述（由申请人提供）：肥胖和糖尿病的发病率正在达到流行病的比例，但其快速扩张的机制尚不完全清楚。数据显示合成化学品的生产和肥胖率之间的相关性，促使一些人提出了“环境致肥胖假说”，这表明一些环境污染物在肥胖症的发展中可能起着致病作用。虽然一些内分泌干扰化学物质已被证明可以促进脂肪细胞的分化，但导致这种现象的确切途径还不完全。以前研究内分泌干扰物对生殖轴影响的工作已经证明，药物可以直接结合并调节核雌激素受体。由于脂肪细胞受到许多转录因子的高度调节，我们将测试内分泌干扰物通过直接调节核转录因子和基因/蛋白质表达变化影响脂肪细胞功能的假设。因此，本申请的首要目标是确定内分泌干扰化学物质影响前脂肪细胞分化和成熟脂肪细胞能量稳态的特定分子机制。这项工作的一个具体重点将是区分通过糖皮质激素受体介导的内分泌干扰物的生理效应相比，过氧化物酶体增殖物激活剂-γ，因为这两种途径对成熟脂肪细胞的胰岛素敏感性有拮抗作用。具体目标1将确定内分泌干扰物，改变特定的核转录因子在前脂肪细胞的活性，并确定其对3 T3-L1前脂肪细胞的分化的影响。还将特别注意通过不同途径发挥作用的内分泌干扰物之间的潜在协同作用，这可能解释接触低剂量的多种化学品如何可能导致不适当的前脂肪细胞分化。具体目标2将描述内分泌干扰物对成熟脂肪细胞中胰岛素介导的能量稳态的影响，包括胰岛素信号级联的激活和葡萄糖摄取、脂肪生成和抗脂解的调节。这一目标的一个特别重点将是确定在特定的发育窗口期间暴露于内分泌干扰物是否会改变成熟脂肪细胞的胰岛素敏感性。公共卫生关系：这项工作将有助于表征环境污染物影响脂肪细胞发育和行为的方式，以了解合成化学物质如何导致肥胖流行;这些研究还可以为肥胖症中脂肪细胞生物学改变的机制提供新的见解。最后，这些研究可以支持公共卫生工作，以补救环境污染。