Adipogenesis and Insulin Resistance

脂肪生成和胰岛素抵抗

• 批准号: 8349647
• 负责人: Arthur Sherman
• 金额: $ 8.02万
• 依托单位: NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8349647
• 关键词: Adipocytes; Adipose tissue; Animal Model; Animals; Cell Differentiation process; Cell Size; Cells; Characteristics; Collaborations; Defect; Deposition; Diabetes Mellitus; Disease; Exhibits; Extramural Activities; Failure; Fatty acid glycerol esters; Filtration; First Degree Relative; Functional disorder; Genes; Goals; Hyperplasia; Hypertrophy; Impairment; Individual; Inflammatory; Insulin; Insulin Resistance; Interleukin-6; Lead; Liver; Metabolic; Modeling; Muscle; Mutation; National Institute of Diabetes and Digestive and Kidney Diseases; Nature; Non-Insulin-Dependent Diabetes Mellitus; Nylons; Obesity; Organ; Overweight; Pancreas; Paper; Pathogenesis; Peroxisome Proliferator-Activated Receptors; Pilot Projects; Pioglitazone; Preparation; Process; Property; Rattus; Recording of previous events; Recruitment Activity; Reporting; Resistance; Risk Factors; Role; Tail; Testing; Time; Work; adipocyte differentiation; adiponectin; diabetic; glucose uptake; insulin sensitizing drugs; lipid biosynthesis; response; rosiglitazone

We continue our collaboration with the Cushman lab (NIDDK) and several extramural labs to analyze cell-size distributions in adipose tissue in order to elucidate relationships between fat cell size and insulin resistance. We previously reported that such distributions are roughly bi-model, with a Gaussian peak of large, mature cells and an exponential tail of small cells. In contrast to prior hypotheses, we were unable to find an association between the size of the large fat cells per se and insulin resistance (IR) when moderately obese subjects are matched for obesity. Rather, we found a correlation between the proportion of large cells and IR, with resistant subjects having a deficit of large cells. We proposed that this reflects an impairment of adipocyte differentiation and leads to insufficient fat storage capacity and ectopic fat deposition in other organs, such as liver, pancreas, and muscle, that are not well equipped to handle large volumes of fat. A reanalysis of these questions with a much larger group of subjects spanning a much wider range of BMI has confirmed the correlation between the proportion of small cells and IR but also showed a correlation between large cell size and IR. We attribute the failure to observe this in the earlier pilot study to the smallnumber of subjects the restricted range of BMI. A paper is in preparation. In collaboration with the Smith lab (Gothenburg) we have found a correlation between the size of the large cells and IR in a group of leaner, younger subjects who were first degree relatives of type 2 diabetics (paper in revision). We suggest that this is because the leaner subjects are still able to expand their adipose cells whereas the more obese subjects have reached the limit of cell expansion (hypertrophy) and must recruit new cells (hyperplasia). Furthermore, administration of insulin-sensitizing drugs, such as pioglitazone or rosiglitazone, leads to both recruitment of new cells, which increases the proportion of small cells, and expansion of existing large cells (paper in preparation). Thus, in all these cases the distribution of adipose cell sizes is related to metabolic status, but the particular response is dependent on the metabolic status and history of the subject. Considering these results together with those from the Stanford group (previous paragraph) and work in other sections of LBM, we conclude that large cell size is a primary risk factor for insulin resistance, along with an excess of small cells, reflecting impaired differentiation. Indeed, the two properties may be related, as a defect in potential to recruit and enlarge new adipocytes may be compensated by enlargement of existing adipocytes beyond their healthy operating range. In collaboration with the McLaughlin lab (Stanford) we have also tested the hypothesis that small adipocytes per se are subject to impaired differentiation and function. Small adipocytes were isolated from epididymal adipose tissue of Zucker Obese (ZO) and Lean (ZL) rats and separated by sequential filtration through nylon meshes. Using quantitative real-time PCR for cell differentiation and inflammatory genes we found that the small cels represented a greater proportion in ZO than ZL rats. The small cells in the ZO rats had decreased adiponectin, and increased visfatin and IL-6 levels. The small adipocytes in the ZO rats also had lower adiponectin and PPARγ levels than in the ZL rats but increased IL-6. We thus confirmed for these animal models that the small adipocytes exhibited impaired cell differentiation and pro-inflammatory activity in addition to being present in higher proportions. We suggest that these properties contribute to insulin resistance in the animals. See Ref. # 1.

我们继续与 Cushman 实验室 (NIDDK) 和几个校外实验室合作，分析脂肪组织中的细胞大小分布，以阐明脂肪细胞大小与胰岛素抵抗之间的关系。 我们之前报道过，这种分布大致是双模型的，具有大的成熟细胞的高斯峰和小细胞的指数尾部。 与之前的假设相反，当中度肥胖受试者与肥胖相匹配时，我们无法发现大脂肪细胞本身的大小与胰岛素抵抗（IR）之间的关联。 相反，我们发现大细胞的比例与 IR 之间存在相关性，耐药受试者存在大细胞缺陷。 我们认为，这反映了脂肪细胞分化受损，导致脂肪储存能力不足和其他器官（如肝脏、胰腺和肌肉）异位脂肪沉积，这些器官没有能力处理大量脂肪。 对涵盖更广泛 BMI 的更大范围受试者对这些问题进行重新分析，证实了小细胞比例与 IR 之间的相关性，但也显示了大细胞大小与 IR 之间的相关性。 我们将早期试点研究中未能观察到这一点的原因归咎于受试者数量较少以及 BMI 范围有限。 一篇论文正在准备中。 我们与史密斯实验室（哥德堡）合作，发现了一组较瘦、较年轻的受试者的大细胞大小与 IR 之间的相关性，这些受试者是 2 型糖尿病患者的一级亲属（论文正在修订中）。 我们认为这是因为较瘦的受试者仍然能够扩增其脂肪细胞，而较肥胖的受试者已达到细胞扩增的极限（肥大）并且必须招募新细胞（增生）。 此外，使用胰岛素增敏药物，如吡格列酮或罗格列酮，会导致新细胞的募集，从而增加小细胞的比例，并导致现有大细胞的扩张（论文正在准备中）。 因此，在所有这些情况下，脂肪细胞大小的分布与代谢状态相关，但特定反应取决于受试者的代谢状态和病史。 考虑到这些结果以及斯坦福大学小组（上一段）和 LBM 其他部门的工作结果，我们得出结论，大细胞大小是胰岛素抵抗的主要危险因素，同时小细胞过多，反映了分化受损。 事实上，这两种特性可能是相关的，因为招募和扩大新脂肪细胞的潜力的缺陷可以通过现有脂肪细胞超出其健康工作范围的扩大来补偿。 我们与麦克劳林实验室（斯坦福大学）合作，还测试了小脂肪细胞本身的分化和功能受损的假设。从 Zucker Obese (ZO) 和 Lean (ZL) 大鼠的附睾脂肪组织中分离小脂肪细胞，并通过尼龙网连续过滤分离。使用定量实时 PCR 检测细胞分化和炎症基因，我们发现 ZO 大鼠中小细胞的比例高于 ZL 大鼠。 ZO 大鼠的小细胞脂联素减少，内脂素和 IL-6 水平增加。 ZO 大鼠的小脂肪细胞的脂联素和 PPARγ 水平也低于 ZL 大鼠，但 IL-6 增加。 因此，我们在这些动物模型中证实，小脂肪细胞除了以较高比例存在外，还表现出受损的细胞分化和促炎活性。 我们认为这些特性会导致动物的胰岛素抵抗。 参见参考文献。 ＃1。