Adipogenesis and Insulin Resistance

我们继续与库什曼实验室（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。 相比之下，我们发现，在一组较瘦的年轻受试者中，他们是2型糖尿病患者的一级亲属，大细胞的大小与胰岛素抵抗呈正相关（论文准备中）。 我们认为这是因为较瘦的受试者仍然能够扩大他们的脂肪细胞，而较肥胖的受试者已经达到细胞扩张的极限（肥大），必须招募新的细胞（增生）。 此外，胰岛素增敏药物（如吡格列酮或罗格列酮）的给药导致新细胞的募集（增加小细胞的比例）和现有大细胞的扩增（论文准备中）。 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，但具体的反应取决于受试者的代谢状态和病史。 我们认为，受试者在脂肪组织中适当储存脂质的能力，以及避免溢出到不具备处理大量脂质的其他组织的能力，是胰岛素敏感性的核心。 我们还与耶鲁大学的Caprio实验室合作，将研究范围扩大到肥胖青少年。 先前的研究表明，胰岛素抵抗与内脏脂肪组织（VAT）相对于总脂肪组织（VAT + SAT，皮下脂肪组织）的高比例或VAT/（VAT + SAT）相关。 此外，这些受试者更有可能表现出肝脏中脂肪的异位存款（肝脂肪变性）。 我们获得了皮下腹部脂肪组织并进行了细胞大小分析，发现具有高VAT/（VAT + SAT）的受试者具有较大的大脂肪细胞，但大细胞的比例较小。 参与脂质代谢的基因的微阵列分析也显示了高VAT/（VAT + SAT）组的缺陷。 虽然在这种类型的研究中无法确定因果关系，但我们认为皮下组织脂质储存受损与胰岛素抵抗有关。 结果已发表在参考文献1中。

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 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. In contrast, we have found that in a group of leaner, younger subjects who were first degree relatives of type 2 diabetics that the size of the large cells is positively correlated with insulin resistance (paper in preparation). 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. We suggest that the ability of subjects to properly store lipids in adipose tissue, and avoid spillover to other tissues not equipped to handle large quantities of lipids, is central to insulin sensitivity. We have also extended our studies to obese adolescents in collaboration with the Caprio lab at Yale. Previous studies had shown that insulin resistance was associated with a high proportion of visceral adipose tissue (VAT) in relation to total adipose tissue (VAT plus SAT, subcutaneous adipose tissue), or VAT/(VAT + SAT). In addition, those subjects were more likely to exhibit ectopic deposit of fat in the liver (hepatic steatosis). We obtained subcutaneous abdominal adipose tissue and carried out a cell size analysis and found that subjects with high VAT/(VAT + SAT) had larger large adipose cells but a smaller proportion of large cells. Microarray analysis of genes involved in lipid metabolism also showed deficiencies in the high VAT/(VAT + SAT) group. Although causation cannot be determined in this type of study, we suggest that impairments in lipid storage in subcutaneous tissue are involved in insulin resistance. The results have been published in Ref. # 1.