Adipogenesis and Insulin Resistance

脂肪生成和胰岛素抵抗

• 批准号: 8148667
• 负责人: Arthur Sherman
• 金额: $ 8.9万
• 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/8148667
• 关键词: Adipocytes; Adipose tissue; Adolescent; Cell Size; Characteristics; Diabetes Mellitus; Disease; Etiology; Exhibits; Extramural Activities; Fatty Liver; Fatty acid glycerol esters; First Degree Relative; Genes; Goals; Hyperplasia; Hypertrophy; Insulin; Insulin Resistance; Microarray Analysis; National Institute of Diabetes and Digestive and Kidney Diseases; Non-Insulin-Dependent Diabetes Mellitus; Organ; Preparation; Process; Recording of previous events; lipid biosynthesis

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.

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，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。 相比之下，我们发现，在一组较瘦、较年轻的 2 型糖尿病患者的一级亲属中，大细胞的大小与胰岛素抵抗呈正相关（论文正在准备中）。 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。 我们认为，受试者在脂肪组织中正确储存脂质并避免溢出到无法处理大量脂质的其他组织的能力对于胰岛素敏感性至关重要。 我们还与耶鲁大学卡普里奥实验室合作，将研究范围扩展到肥胖青少年。 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 加 SAT，皮下脂肪组织）或 VAT/(VAT + SAT) 的高比例相关。 此外，这些受试者更有可能在肝脏中出现脂肪异位沉积（肝脂肪变性）。 我们获取了皮下腹部脂肪组织并进行了细胞大小分析，发现VAT/（VAT + SAT）高的受试者具有较大的大脂肪细胞，但大细胞比例较小。 对脂质代谢相关基因的微阵列分析也显示高 VAT/(VAT + SAT) 组存在缺陷。 尽管此类研究无法确定因果关系，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中。 ＃1。