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; 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具有独特的尺寸分布。 它不是一个典型的单峰高斯分布，而是大细胞的高斯峰和小细胞的指数状尾巴。 我们已经将高斯峰解释为代表成熟的脂肪细胞，而尾巴则是较新的细胞，它们在吸收脂质的过程中生长。 在某些个体（人和啮齿动物）中，可以观察到具有中等直径的细胞的额外峰，甚至可能随着时间的推移向右移动，这表明会在随着时间的推移一起募集的细胞推注，并与成熟细胞的峰一起生长并连接到成熟的细胞峰。 我们已经将大小分布的特征（主要是小细胞的比例和大细胞的典型大小）相关联，在各种研究人群中具有胰岛素抵抗或敏感性。 我们的最初研究与斯坦福大学的麦克劳克林实验室合作研究了对胰岛素敏感（IS）或胰岛素耐药（IR）的中等肥胖受试者（BMI接近30 kg/m2），发现胰岛素耐药组的小细胞比例增加了小细胞的比例。 这被解释为脂肪细胞发育受损的签名，这可能会导致脂质储存能力受损，并导致脂质溢出到其他功能不佳的器官以应对脂肪负载。 已经提出了这种溢出剂或“异位脂肪”在胰腺中引起肌肉和肝脏胰岛素耐药性的胰岛素耐药性。 该研究指出，IR受试者中大型大细胞的趋势，但这并未达到统计学意义。 如果BMI和总脂肪质量在两组之间相同，那么人们会期望较大的大细胞，并且与设计一样。 对较大的受试者和更广泛的BMI的后续研究证实了小细胞和较大的大细胞的比例增加（参见2014年报告的参考文献＃1）。 我们在参考文献中也报告了大小的增加。 2012年报告的＃1。 来自其他研究的大量证据支持了这样一种观念，即大细胞本质上比小细胞效率较低。 我们的合作者获得了支持上述通用模型预测的进一步数据，即削弱了脂肪细胞的差异与胰岛素抵抗有关（Liu等，PLOS One 12（2）：E0170728，2017，PubMed ID，PubMed ID：28151993）。 使用接受减肥手术的患者的内脏和皮下脂肪，他们表明，通过油红O染色和脂肪生成基因表达评估的脂肪细胞的分化程度较低，在胰岛素抵抗受试者中较低。 同样，在CD14+巨噬细胞中培养前脂肪细胞，减少了分化标记。 这支持了其他人的发现，即炎症与胰岛素抵抗有关，并可能导致胰岛素的耐药性。