Adipogenesis and Insulin Resistance

近十年来，我们一直在许多环境中研究胰岛素抵抗和脂肪细胞大小之间的关系。我们从这些调查中提炼出的主要想法包括： 1.脂肪细胞的大小差异很大，从直径约20微米到远超过100微米，适合它们作为细胞的独特角色，这些细胞可以根据需要膨胀和收缩，以吸收和释放脂肪。 2.这些分布不是典型的单峰高斯分布，而是典型的大单元的高斯型峰值和小单元的指数型尾部。我们将高斯峰解释为成熟的脂肪细胞，将尾巴解释为正在生长过程中的新细胞，因为它们吸收了脂肪。实验室中其他人的动力学模型(见Vipul Periwal，LBM的报告)证实，假想的生长过程包括新出现的直径约20微米的细胞，并根据大小相关的生长规律生长，自然会产生这种分布。如果假设细胞生长缓慢，直到达到例如30-60微米的门槛直径，然后快速生长，那么在左尾和右峰之间就会发现一个明显的最低点。在一些个体中，无论是人类还是啮齿动物，都可以观察到一个中等直径的细胞的额外峰值，该峰值甚至可能随着时间的推移向右移动，这表明在时间上招募的细胞团在一起生长并加入成熟细胞的峰值。 3.在不同的研究人群中，我们将大小分布的特征，主要是小细胞的比例和大细胞的典型大小，与胰岛素抵抗或敏感性联系起来。我们最初的研究与斯坦福大学的麦克劳克林实验室合作，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公斤/平方米)，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，这可能导致脂肪储存能力受损，并导致脂肪溢出到其他没有配备来处理脂肪负荷的器官。这种溢出，或“异位脂肪”，已被提出导致肌肉和肝脏的胰岛素抵抗，并损害胰腺的胰岛素分泌。这项研究注意到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。如果两组之间的BMI和总脂肪质量相同，正如设计的那样，人们预计会有更大的大细胞，而大细胞所占的比例较小。一项对更大范围的受试者和更大范围的BMI进行的后续研究证实了小细胞和大细胞比例的增加(见参考文献)。本报告的第一条)。我们在参考文献中也报道了增加的大小。2012年报告的第一名。来自其他研究的大量证据支持这样的观点，即大细胞在储存脂肪方面的效率本质上低于小细胞(同样，参见LBM Periwal的报告，了解这一理论观点)。 总而言之，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。上述结果与LBM其他部分的工作结合在一起，得出了总体结论，即大细胞尺寸是胰岛素抵抗的主要风险因素，小细胞过多也是主要风险因素。我们假设，在未经治疗的IR受试者中，小细胞的过剩反映了分化受损。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。

For nearly the past decade we have been studying the relationship between insulin resistance and adipocyte size in a number of settings. The key ideas we have distilled from these investigations include: 1. Adipose cells vary widely in size from about 20 microns in diameter to well over 100 microns, befitting their unique role as cells that can expand and contract to take up and release lipid as needed. 2. The distributions are not typical unimodal Gaussian distributions but typically have 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. Dynamical models by others in the lab (see reports by Vipul Periwal, LBM) have confirmed that a hypothesized growth process incorporating newly recruited cells emerging with diameter around 20 microns and growing according to a size-dependent growth law naturally generates such distributions. A distinct nadir between the left tail and the right peak is found if cells are assume to grow slowly until they reach a threshold diameter of, say, 30 - 60 microns and then grow rapidly. 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. 3. 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 this 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 (again, see report of Periwal, LBM, for a theoretical view of this). In summary, 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. The results above, taken together, along with work in other sections of LBM, lead to the overall conclusion that large cell size is a primary risk factor for insulin resistance, along with an excess of small cells. We hypothesize that in untreated IR subjects the surplus of small cells reflects 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.