Adipogenesis and Insulin Resistance

我们继续与Cushman（NIDDK）和Reaven（斯坦福大学）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。 我们以前报道过，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。 与先前的假设相反，我们发现，当中度肥胖受试者与肥胖相匹配时，大脂肪细胞本身的大小与胰岛素抵抗（IR）无关。 相反，我们发现大细胞的比例与IR之间存在相关性，耐药受试者缺乏大细胞。 我们认为，这反映了脂肪细胞分化受损，并导致脂肪储存能力不足和其他器官（如肝脏、胰腺和肌肉）中的异位脂肪沉积，这些器官没有很好的装备来处理大量脂肪。 对胰岛素敏感和抵抗受试者的进一步横断面研究已经检查了IR和炎症基因表达之间的关系。 我们研究了14名IR和19名IS中度肥胖女性（参考文献#2）。 IR组中与炎症相关的几个基因（CD 68、EMR 1、IL 8、IL 6和MCP/CCL 2）显着增加。 我们还研究了炎症基因表达和细胞大小特征之间的关系。 我们发现炎症和IR与大细胞比例的降低独立相关（参考文献#3）。 与其他研究相比，我们没有发现大细胞亚群的大小与炎症之间的关系。 因此，我们的研究不支持炎症与较大脂肪细胞相关的假设，至少在中度肥胖个体中是这样。 总之，IR、炎症和大细胞比例减少这三个特性似乎形成了一个三角形复合体。 需要进一步的工作来确定炎症是否损害脂肪细胞分化或受损的分化易患炎症。 上述研究使用皮下脂肪组织（SAT）进行，但我们也能够从减肥手术患者（11名女性;参考文献#1）中获得内脏脂肪组织（VAT）样本。 我们发现SAT细胞比VAT细胞大。 有趣的是，在SAT中，大细胞的大小随着小细胞的百分比而增加，这可能反映了脂肪量的一种守恒形式：一定量的脂肪可以储存在许多小细胞或少数大细胞中。 这种关系在VAT中并不成立，这可能表明VAT主要不是一个全球存储机构，而是服务于一组不同的功能，例如信号或本地存储。 我们还发现，相对于SAT，VAT中的几种炎症标志物增加。 我们还将这些研究扩展到胰岛素增敏剂吡格列酮的干预（参考文献4）。 我们发现，药物导致小细胞比例的增加，这可能反映了前体细胞增加了新脂肪细胞的募集。为了支持这一点，皮下组织的CT扫描结合细胞大小的分布使我们能够估计每个细胞的平均体积以及小细胞和大细胞的数量。 这种药物增加了小细胞的数量，但没有减少大细胞的数量。尽管这似乎与先前报道的胰岛素敏感受试者中大细胞比例较高表面上不一致，但我们注意到，通过药物治疗改善胰岛素抵抗不一定使胰岛素抵抗受试者的代谢状态恢复到正常受试者的代谢状态。 这一发现也与观察结果一致，即受试者的内脏脂肪组织体积减少，腹部皮下脂肪组织体积增加，表明通过招募新的小皮下细胞，脂肪从一个隔室转移到另一个隔室。 最后，新招募的小细胞最终可能会积累更多的脂肪并变得更大。 需要进一步的研究来确定小细胞的生物活性是否不同于大细胞。

We continue our collaboration with the Cushman (NIDDK) and Reaven (Stanford) 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 found that the size of the large fat cells per se is not associated with 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. Further cross-sectional study of insulin-sensitive and resistant subjects has examined the relationship between IR and expression of inflammation genes. We studied 14 IR and 19 IS moderately obese women (Ref. #2). Several genes associated with inflammation (CD68, EMR1, IL8, IL6, and MCP/CCL2)were significantly increased in the IR group. We also investigated the relationship between inflammation gene expression and cell size characteristics. We found that inflammation and IR are independently associated with a reduced proportion of large cells (Ref. # 3). In contrast to other studies, we did not find a relationship between the size of the large cell sub-population and inflammation. Thus, our study does not support the hypothesis that inflammation is associated with larger adipose cells, at least in moderately obese individuals. In sum three properties, IR, inflammation, and diminished large-cell proportion, thus seem to form a triangular complex. Further work is needed to determine whether inflammation impairs adipose cell differentiation or impaired differentiation predisposes to inflammation. The above studies were conducted using subcutaneous adipose tissue (SAT), but we were able to obtain samples of visceral adipose tissue (VAT) as well from bariatric surgery patients (11 females; Ref. # 1). We found that the SAT cells were larger than the VAT cells. Interestingly, in SAT, the size of the large cells increased with the percentage of small cells, which may reflect a form of conservation of fat mass: a given amount of fat can be stored in many small cells or few large cells. This relationship did not hold in VAT, which may indicate that VAT is not primarily a global storage organ but serves a different set of functions, such as signaling or local storage. We also found that several inflammation markers were increased in VAT relative to SAT. We have also extended these studies to intervention with the insulin sensitizer, pioglitazone (Ref. # 4). We found that the drug led to an increase of the proportion of small cells, perhaps reflecting increased recruitment of new adipocytes from precursor cells. In support of this, CT scans of subcutaneous tissue combined with the distribution of cell size allowed us to estimate the average volume per cell and the numbers of small and large cells. The drug increased the number of small cells but did not reduce the number of large cells. Although this seems superficially at odds with the previously reported higher proportion of large cells in insulin sensitive subjects, we note that amelioration of insulin resistance by drug treatment does not necessarily restore the metabolic state of an insulin resistant subject to that of a normal subject. The finding is also consistent with the observation that the subjects experienced a decrease of visceral adipose tissue volume and an increase in abdominal subcutaneous adipose tissue volume, suggesting a transfer of fat from one compartment to the other permitted by the recruitment of new small subcutaneous cells. Finally, it is possible that the newly recruited small cells would eventually accumulate more fat and become large. Further study is needed to determine whether the biological activity of the small cells is different from that of the large cells.