Adipogenesis and Insulin Resistance

我们研究的主要发现之一是脂肪细胞具有独特的大小分布。 它不是典型的单峰高斯分布，但具有大细胞的高斯样峰和小细胞的指数样尾。 我们已经将高斯峰解释为代表成熟的脂肪细胞，并且将尾部解释为随着它们摄取脂质而处于生长过程中的新细胞。 在一些个体中，无论是人类还是啮齿动物，都可以观察到具有中等直径的细胞的额外峰，其甚至可以随时间向右移动，这表明在时间上聚集在一起的细胞团生长并加入成熟细胞的峰。 我们已经将大小分布的特征，主要是小细胞的分数和大细胞的典型大小，与各种研究人群中的胰岛素抵抗或敏感性相关联。 我们与斯坦福大学McLaughlin实验室合作的初步研究，检查了胰岛素敏感（IS）或胰岛素抵抗（IR）的中度肥胖受试者（BMI接近30 kg/m2），发现胰岛素抵抗组的小细胞比例增加。 这被解释为脂肪细胞发育受损的标志，这可能导致脂质储存能力受损，并导致脂质溢出到其他器官，无法处理脂肪负荷。 这种溢出或“异位脂肪”被认为会导致肌肉和肝脏中的胰岛素抵抗以及胰腺中胰岛素分泌受损。 该研究注意到IR受试者中有更大的大细胞的趋势，但这并没有达到统计学意义。 如果两组的BMI和总脂肪量相同，那么如果大细胞的比例较小，那么大细胞会更大。 一项针对更大受试者组和更广泛BMI范围的随访研究证实了小细胞和较大大细胞的比例增加（参见2014年报告的参考文献#1）。 我们还在2012年报告的参考文献1中报告了增加的尺寸。 来自其他研究的大量证据支持这样的观点，即大细胞在储存脂质方面本质上不如小细胞有效。 我们的合作者已经获得了进一步的数据，支持上述一般模型的预测，即前脂肪细胞的分化受损与胰岛素抵抗有关（Liu et al，PLoS One 12（2）：e0170728，2017，Pubmed ID：28151993）。 他们使用接受减肥手术的患者的内脏和皮下脂肪，通过油红O染色和成脂基因表达评估，他们发现胰岛素抵抗受试者的前脂肪细胞分化程度较低。 此外，在CD 14+巨噬细胞中培养前脂肪细胞减少了分化标志物。 这支持了其他人的发现，即炎症与胰岛素抵抗有关，并可能是胰岛素抵抗的原因。

One of the main findings of our research is that adipose cells have a unique size distribution. It is not a typical unimodal Gaussian distribution but has a Gaussian-like peak of large cells and an exponential-like tail of small cells. We have interpreted the Gaussian peak as representing mature adipocytes and the tail as newer cells in the process of growing as they take up lipid. In some individuals, both human and rodent, an additional peak of cells with intermediate diameter can be observed, which may even move to the right with time, suggesting a bolus of cells recruited close together in time that grows and joins the peak of mature cells. We have correlated the characteristics of the size distributions, chiefly the fraction of small cells and the typical size of the large cells, with insulin resistance or sensitivity in a variety of study populations. Our initial study, in collaboration with the McLaughlin lab at Stanford University, examined moderately obese subjects (BMI near 30 kg/m2) who were insulin sensitive (IS) or insulin resistant (IR) and found that the insulin resistant group had an increased proportion of small cells. This was interpreted as a signature of impaired adipocyte development, which could result in impaired lipid storage capacity and lead to spillover of lipid to other organs poorly equipped to handle the fat load. Such spillover, or "ectopic fat" has been proposed to cause insulin resistance in muscle and liver and impaired insulin secretion in the pancreas. The study noted a trend toward larger large cells among the IR subjects, but this did not reach statistical significance. One would expect larger large cells given a smaller proportion of large cells if BMI and total fat mass are the same between the groups, as they were by design. A follow-up study with a larger group of subjects and a broader range of BMI has confirmed the increased proportion of small cells as well as larger large cells (see Ref. # 1 of the 2014 report). The increased size was also reported by us in Ref. # 1 of the 2012 report. A considerable body of evidence from other studies supports the notion that large cells are intrinsically less efficient at storing lipid than small cells. Our collaborators have obtained further data supporting the prediction of the above general model that impaired differentiation of pre-adipocytes is related to insulin resistance (Liu et al, PLoS One 12(2):e0170728, 2017, Pubmed ID: 28151993). Using visceral and subcutaneous adipose from patients undergoing bariatric surgery, they showed that the degree of differentiation of pre-adipocytes, assessed by Oil Red O staining and adipogenic gene expression, was lower in insulin resistant subjects. Also, culturing pre-adipocytes in CD14+ macrophages, reduced markers of differentiation. This supports the findings of others that inflammation is associated with, and possibly causative of, insulin resistance.