Adipogenesis and Insulin Resistance

我们继续与Cushman实验室(NIDDK)和几个校外实验室合作，分析脂肪组织中细胞大小的分布，以阐明脂肪细胞大小和胰岛素抵抗之间的关系。我们以前报道过这样的分布大致是双模型的，大的成熟细胞的高斯峰和小细胞的指数尾巴。与之前的假设相反，当中度肥胖的受试者与肥胖匹配时，我们无法找到大型脂肪细胞本身的大小与胰岛素抵抗(IR)之间的联系。相反，我们发现了大细胞比例和IR之间的相关性，耐药受试者有大细胞缺陷。我们认为，这反映了脂肪细胞分化的损害，并导致脂肪储存能力不足，以及其他器官，如肝脏、胰腺和肌肉中异位脂肪沉积，这些器官不具备处理大量脂肪的良好条件。对这些问题的重新分析，涉及更大范围的BMI，证实了小细胞比例与胰岛素抵抗之间的相关性，但也显示了大细胞尺寸与胰岛素抵抗之间的相关性。我们将早期试点研究中未能观察到这一点归因于受试者数量较少，体重指数的范围有限。一篇论文正在准备中。 在与史密斯实验室(哥德堡)的合作中，我们在一组更瘦、更年轻的受试者中发现了大细胞的大小和胰岛素抵抗之间的相关性，这些受试者是2型糖尿病患者的一级亲属(论文修订中)。我们认为，这是因为较瘦的受试者仍然能够扩张他们的脂肪细胞，而较肥胖的受试者已经达到细胞扩张(肥大)的极限，必须招募新的细胞(增生)。此外，给予胰岛素增敏药物，如吡格列酮或罗格列酮，既会导致新细胞的招募，从而增加小细胞的比例，又会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有关，但特定的反应取决于受试者的代谢状态和病史。结合斯坦福大学研究小组(上一段)和LBM其他部分的研究结果，我们得出结论：大细胞是胰岛素抵抗的主要风险因素，小细胞过多反映分化受损。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扩大现有脂肪细胞的健康工作范围来弥补。 在与麦克劳克林实验室(斯坦福大学)的合作中，我们还测试了小脂肪细胞本身受到分化和功能损害的假设。从Zucker obese(ZO)和Lean(ZL)大鼠附睾脂肪组织中分离小脂肪细胞，并用尼龙网连续过滤分离。用实时荧光定量聚合酶链式反应检测细胞分化和炎症基因，发现ZO大鼠的小细胞所占比例高于ZL大鼠。ZO大鼠小细胞脂联素水平降低，内脂素和IL-6水平升高。ZO大鼠的小脂肪细胞的脂联素和PPAR水平也低于ZL大鼠，但IL-6水平升高。因此，对于这些动物模型，我们证实了小脂肪细胞除了以较高比例存在外，还表现出细胞分化和促炎活性受损。我们认为这些特性导致了动物的胰岛素抵抗。参见参考文献#1.

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.