Adipogenesis and Insulin Resistance

脂肪生成和胰岛素抵抗

• 批准号: 9553212
• 负责人: Arthur Sherman
• 金额: $ 3.96万
• 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/9553212
• 关键词: Adipocytes; Adipose tissue; Bolus Infusion; CD14 gene; Caliber; Cells; Characteristics; Collaborations; Data; Diabetes Mellitus; Differentiation Antigens; Disease; Fatty acid glycerol esters; Follow-Up Studies; Functional disorder; Gaussian model; Gene Expression; Goals; Human; Impairment; Individual; Inflammation; Insulin; Insulin Resistance; Lead; Lipids; Liver; Modeling; Muscle; Mutation; Nature; Non-Insulin-Dependent Diabetes Mellitus; Normal Statistical Distribution; Obesity; Oils; Organ; Overweight; Pancreas; Pathogenesis; Patients; Process; PubMed; Recruitment Activity; Reporting; Research; Risk Factors; Rodent; Role; Staining method; Stains; Tail; Thinness; Time; Universities; Visceral; adipocyte differentiation; bariatric surgery; design; glucose uptake; insulin secretion; insulin sensitivity; lipid biosynthesis; macrophage; study population; subcutaneous; trend

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.

我们研究的主要发现之一是脂肪细胞有独特的大小分布。它不是典型的单峰高斯分布，而是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。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。 我们已经在不同的研究人群中将大小分布的特征，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)。2014年报告的第一条)。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天生不如小细胞有效。 我们的合作者获得了进一步的数据，支持上述一般模型的预测，即前脂肪细胞分化受损与胰岛素抵抗有关(Liu等，PLoS one 12(2)：E0170728,2017年，Pubmed ID：28151993)。使用减肥手术患者的内脏和皮下脂肪，他们显示，在胰岛素抵抗的受试者中，通过油红O染色和成脂基因表达来评估前脂肪细胞的分化程度较低。此外，在CD14+的巨噬细胞中培养前脂肪细胞，减少了分化的标志。这支持了其他人的发现，即炎症与胰岛素抵抗有关，并可能导致胰岛素抵抗。