Cellular Dynamics of Subcutaneous Fat Distribution in Obese Women

肥胖女性皮下脂肪分布的细胞动力学

• 批准号: 8440368
• 负责人: Eric Ravussin
• 金额: $ 35.88万
• 依托单位: LSU PENNINGTON BIOMEDICAL RESEARCH CTR
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-04-01 至 2016-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8440368
• 关键词: 2,4-thiazolidinedione; Abdomen; Adipocytes; Adipose tissue; Agonist; Antidiabetic Drugs; Apple; Biomedical Research; Blood Vessels; Body fat; Cell Aging; Cell Culture Techniques; Cells; Chronic; Comorbidity; Coupled; DNA; Data; Deposition; Deuterium; Development; Environment; Environmental Risk Factor; Event; Fatty acid glycerol esters; Goals; Growth; Health; Hip region structure; Human; Hyperplasia; Hypertrophy; Individual; Inflammatory; Inflammatory Response; Insulin Resistance; Intervention; Intrinsic factor; Kinetics; Lead; Leg; Longevity; Longitudinal Studies; Measures; Mediating; Metabolic; Morphology; Obesity; Pear; Phenotype; Physiology; Pioglitazone; Placebos; Plastics; Prevention; Prevention strategy; Regulation; Reporting; Research; Research Personnel; Risk; Shapes; Signal Transduction; Site; Stimulus; Tail; Techniques; Testing; Thiazolidinediones; Waist-Hip Ratio; Weight; Woman; Work; adipokines; drinking water; experience; glycemic control; improved; in vivo; lipid biosynthesis; metabolic abnormality assessment; prevent; progenitor; public health relevance; response; stable isotope; subcutaneous; tool

DESCRIPTION (provided by applicant): Adipose tissue expandability and the distribution of stored fat in the body are stronger predictors of health risk. A better understanding of the factors that determine regional fat mass growth may lead to developing new strategies for prevention or treatment of metabolic complications of obesity. The objective of this proposal is to study the responsiveness of lower- body fat mass, the inflammatory state of upper-body fat, ectopic fat, and insulin resistance to adipogenic stimulation in upper-body obese (UBO) women waist-to hip ratio (WHR) >0.85 and lower-body obese (LBO) women with WHR <0.75. Adipogenesis will be stimulated using pioglitazone (Pio). The hypothesis is that in UBO; adipogenesis in femoral fat is impaired, which leads to ectopic fat deposition, promoting insulin resistance. On the other hand, the ScA depot in UBO undergoes hypertrophy, leading to a chronic inflammatory state of the adipose tissue and consequential insulin resistance. Our specific aims are to test that: Aim 1. Impaired adipogenesis in the Sc fat of UBO women contributes to impaired adipogenesis in UBO women and to a) Limited leg fat expandability, which promotes insulin resistance via ectopic fat deposition; and b) The inflammatory response of upper-body fat which contributes to insulin resistance via inflammatory adipokines.; Aim 2. Cellular senescence contributes to impaired adipogenesis in UBO women and to identify candidate intrinsic or environmental factors that cause the depot-specific adipogenic regulation. UBO and LBO women (30 each) will be treated with Pio or placebo for 16 weeks. The adipocyte progenitor number, adipogenesis, the morphology and inflammatory response of adipose tissue, and systemic glycemic control will be determined before, during, and after the intervention. Distribution of fat in fat depots and ectopic sites will be measured. Stromal vascular cultures will be employed to assess preadipocyte kinetics in ScA and Sc femoral (ScF) fat depots and the mechanisms of their regulation. We will also assess in vivo Sc regional adipogenesis by measuring incorporation of deuterium (D) from D2O drinking water into the DNA of plastic adherent stroma-vascular (SV) cells by determining their fractional replacement (fSV cells).

描述（由申请人提供）：脂肪组织的扩张性和体内储存脂肪的分布是健康风险的更强预测因素。更好地了解决定区域脂肪量增长的因素可能会导致制定预防或治疗肥胖代谢并发症的新策略。本提案的目的是研究上半身肥胖 (UBO) 女性腰臀比 (UBO) 的下半身脂肪量、上半身脂肪的炎症状态、异位脂肪和胰岛素抵抗对脂肪生成刺激的反应性。腰臀比 (WHR) >0.85 和腰臀比 (WHR) <0.75 的下半身肥胖 (LBO) 女性。使用吡格列酮 (Pio) 刺激脂肪生成。假设在 UBO 中；股骨脂肪的脂肪生成受损，导致异位脂肪沉积，促进胰岛素抵抗。另一方面，UBO 中的 ScA 库发生肥大，导致脂肪组织的慢性炎症状态和随之而来的胰岛素抵抗。我们的具体目标是测试： 目标 1. UBO 女性 SC 脂肪中的脂肪生成受损会导致 UBO 女性脂肪生成受损，并导致 a) 腿部脂肪扩张能力有限，从而通过异位脂肪沉积促进胰岛素抵抗； b) 上身脂肪的炎症反应，通过炎症脂肪因子导致胰岛素抵抗。目标 2. 细胞衰老导致 UBO 女性脂肪生成受损，并确定导致储库特异性脂肪生成调节的候选内在或环境因素。 UBO 和 LBO 女性（各 30 名）将接受 Pio 或安慰剂治疗 16 周。将在干预之前、期间和之后确定脂肪细胞祖细胞数量、脂肪生成、脂肪组织的形态和炎症反应以及全身血糖控制。将测量脂肪库和异位部位的脂肪分布。基质血管培养物将用于评估 ScA 和 Sc 股骨 (ScF) 脂肪库中的前脂肪细胞动力学及其调节机制。我们还将通过测定 D2O 饮用水中的氘 (D) 掺入塑料贴壁基质血管 (SV) 细胞的 DNA 中，并确定其替代分数（fSV 细胞）来评估体内 Sc 区域脂肪生成。