Adipose tissue inflammation and estrogen synthesis

脂肪组织炎症与雌激素合成

• 批准号: 8105433
• 负责人: Mario Kratz
• 金额: $ 21.97万
• 依托单位: FRED HUTCHINSON CANCER RESEARCH CENTER
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-07 至 2013-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8105433
• 关键词: Abdomen; Adipocytes; Adipose tissue; Androgens; Anti-Inflammatory Agents; Anti-inflammatory; Area; Aromatase; Benign; Biology; Biopsy; Body Weight decreased; Body fat; Breast; C-reactive protein; Cardiovascular Diseases; Cell Count; Cell Fraction; Cell Separation; Cell surface; Cells; Cholecystectomy; Chronic; Colon; Control Groups; Data; Dendritic Cells; Dietary Intervention; Disease; Endometrial Carcinoma; Endothelial Cells; Enzymes; Estradiol; Estrogens; FCGR3B gene; Fatty acid glycerol esters; Fc Receptor; Flow Cytometry; Fluorescence-Activated Cell Sorting; Gene Expression; Goals; Hernia; Heterogeneity; Homeostasis; Hormones; Human; Immune; In Vitro; Individual; Infiltration; Inflammation; Inflammation Mediators; Inflammatory; Insulin; Insulin Resistance; Interleukin-6; Intervention Studies; Link; Malignant Neoplasms; Measures; Menopause; Mesentery; Metabolic; Modeling; Mus; Non obese; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Operative Surgical Procedures; Pancreas; Pilot Projects; Plasma; Population; Postmenopause; Process; Production; Relative (related person); Risk; Risk Factors; Sampling; Serum; Signal Transduction; Sorting - Cell Movement; Source; T-Lymphocyte; TNFR-Fc fusion protein; Tissue Sample; Tissues; Tumor Necrosis Factor-alpha; Up-Regulation; Variant; Weight; Woman; Work; adiponectin; bariatric surgery; base; cancer type; cell type; cytokine; design; granulocyte; high risk; improved; indexing; interest; macrophage; malignant breast neoplasm; men; mouse model; neutrophil; public health relevance; repaired; research study; subcutaneous

DESCRIPTION (provided by applicant): Obesity is now recognized as a risk factor for several types of cancer, including postmenopausal breast and endometrial cancer. Both have been linked to an increased synthesis of estrogens in obese women. Although it is known that extragonadal aromatization of androgens to estrogens after menopause occurs largely in adipose tissue, the mechanisms linking excess adiposity to increased estrogen synthesis are not clear. Specifically, it is unclear which cells synthesize estrogen, and whether specific changes in adipose tissue biology in obesity contribute to the increased estrogen synthesis. Of particular interest, obesity is now known to be associated with adipose tissue infiltration of immune cells such as macrophages, T-cells, and dendritic cells. Experiments largely done in mouse models of obesity have shown that this inflammation of adipose tissue is the primary mechanism by which obesity causes systemic inflammation and insulin resistance. It has remained largely unclear, however, whether the obesity-associated increase in serum estrogen is also caused by adipose tissue inflammation. The hypothesis underlying this proposal is that immune cells infiltrating adipose tissue as part of the obesity-associated inflammation of that tissue express the estrogen- synthesizing hormone aromatase, and/or stimulate aromatase expression in resident cells. We will obtain omental and subcutaneous abdominal adipose tissue from 16 morbidly obese postmenopausal women undergoing bariatric surgery, and by subcutaneous biopsy following weight loss 12 months later. Baseline samples will be compared to those obtained from 16 leaner postmenopausal women free of chronic metabolic and inflammatory disease who undergo elective surgery such as cholecystectomy or hernia repair. Cells present in the stromavascular fraction of adipose tissue will be characterized by flow cytometry, and the different immune cell populations will be collected by fluorescence-activated cell sorting. Gene expression of aromatase as well as mediators of inflammation such as tumor necrosis factor a (TNFa) will be measured in sorted cells, adipocytes, and whole adipose tissue. The concentrations of androgens and estrogens will be measured in adipose tissue and serum samples. We hypothesize that aromatase as well as mediators of inflammation such as TNFa will be expressed in immune cells present in adipose tissue, that the numbers of these cells will be higher in adipose tissue samples of morbidly obese women, and that the number of those cells as well as their inflammatory activity will be reduced by weight loss. This reduction in adipose tissue inflammation will be associated with a reduced expression of aromatase and lower adipose tissue and serum concentrations of estrogens. Identifying the cell types expressing aromatase in adipose tissue, the differences between different fat tissue depots, as well as the link between estrogen synthesis and obesity- associated inflammation will be an important first step in furthering our understanding of the metabolic and cellular mechanisms linking obesity to postmenopausal breast and endometrial cancer. PUBLIC HEALTH RELEVANCE: After menopause, obese women have a higher risk of certain types of cancer, including breast and endometrial cancer. It is thought that increased estrogen synthesis in the expanded fat tissue largely causes this increased risk. We propose a study in lean to morbidly obese postmenopausal women to investigate why fat tissue in obese women produces more estrogen, and which cell types in fat tissue are involved in this process.

描述(申请人提供)：肥胖现在被认为是几种癌症的危险因素，包括绝经后乳腺癌和子宫内膜癌。两者都与肥胖女性雌激素合成增加有关。虽然已知绝经后雄激素在性腺外芳构化为雌激素主要发生在脂肪组织中，但过度肥胖与雌激素合成增加之间的联系机制尚不清楚。具体地说，目前尚不清楚哪些细胞合成雌激素，以及肥胖时脂肪组织生物学的特定变化是否有助于雌激素合成的增加。特别令人感兴趣的是，现在已知肥胖与脂肪组织中巨噬细胞、T细胞和树突状细胞等免疫细胞的渗透有关。在肥胖小鼠模型上进行的大量实验表明，脂肪组织的这种炎症是肥胖导致全身炎症和胰岛素抵抗的主要机制。然而，肥胖相关的血清雌激素水平的增加是否也是由脂肪组织炎症引起的，目前仍不清楚。这一提议背后的假设是，作为肥胖相关炎症的一部分，免疫细胞渗透到脂肪组织中，表达雌激素合成激素芳香化酶，和/或刺激常驻细胞中芳香化酶的表达。我们将从16名接受减肥手术的绝经后病态肥胖妇女身上获取大网膜和皮下脂肪组织，并在12个月后进行体重减轻后的皮下活检。基线样本将与16名没有慢性代谢性和炎症性疾病的绝经后较瘦女性的样本进行比较，这些女性接受了选择性手术，如胆囊切除术或疝气修补。存在于脂肪组织间质血管部分的细胞将通过流式细胞仪进行表征，不同的免疫细胞群将通过荧光激活的细胞分选来收集。将在分选的细胞、脂肪细胞和整个脂肪组织中测量芳香化酶和炎症介质如肿瘤坏死因子a(TNFa)的基因表达。将在脂肪组织和血清样本中测量雄激素和雌激素的浓度。我们假设芳香酶和炎症介质如TNFa将在脂肪组织中的免疫细胞中表达，这些细胞在病态肥胖女性的脂肪组织样本中的数量将会更高，这些细胞的数量以及它们的炎症活性将随着体重的减轻而减少。脂肪组织炎症的减少将与芳香酶表达的减少以及脂肪组织和血清雌激素浓度的降低有关。识别脂肪组织中表达芳香化酶的细胞类型，不同脂肪组织之间的差异，以及雌激素合成与肥胖相关炎症之间的联系，将是进一步了解肥胖与绝经后乳腺癌和子宫内膜癌之间代谢和细胞机制的重要第一步。 公共卫生相关性：绝经后，肥胖女性患某些类型癌症的风险更高，包括乳腺癌和子宫内膜癌。据认为，膨胀的脂肪组织中雌激素合成增加在很大程度上导致了这种风险的增加。我们建议在绝经后瘦到病态肥胖的女性中进行一项研究，以调查为什么肥胖女性的脂肪组织会产生更多的雌激素，以及脂肪组织中的哪些细胞类型参与了这一过程。