Cellular Dynamics of Subcutaneous Fat Distribution in Obese Women

描述（由申请人提供）：脂肪组织扩张性和体内储存脂肪的分布是健康风险的更强预测因子。更好地了解决定局部脂肪量增长的因素可能会导致开发新的策略，用于预防或治疗肥胖的代谢并发症。该提案的目的是研究腰臀比（WHR）>0.85的上身肥胖（UBO）女性和腰臀比<0.75的下身肥胖（LBO）女性的下身脂肪量、上身脂肪的炎症状态、异位脂肪和胰岛素抵抗对成脂刺激的反应性。将使用吡格列酮（Pio）刺激脂肪生成。假设在UBO中，股骨脂肪中的脂肪形成受损，这导致异位脂肪沉积，促进胰岛素抵抗。另一方面，UBO中的ScA贮库经历肥大，导致脂肪组织的慢性炎症状态和相应的胰岛素抵抗。我们的具体目标是测试：目标1。UBO女性Sc脂肪中脂肪生成受损导致UBO女性脂肪生成受损，并导致a）腿部脂肪扩张性有限，通过异位脂肪沉积促进胰岛素抵抗;和B）上身脂肪的炎症反应，通过炎症性脂肪因子导致胰岛素抵抗。目标二。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。将采用基质血管培养物评估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。我们还将通过测定塑料粘附基质-血管（SV）细胞的置换分数（fSV细胞）来测量来自D2 O饮用水的氘（D）掺入塑料粘附基质-血管（SV）细胞的DNA中来评估体内Sc区域脂肪形成。

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).