Adipogenesis and Insulin Resistance

脂肪生成和胰岛素抵抗

基本信息

批准号：
8349647
负责人：
Arthur Sherman
金额：
$ 8.02万
依托单位：
NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES
依托单位国家：
美国
项目类别：
财政年份：
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/8349647
关键词：
Adipocytes Adipose tissue Animal Model Animals Cell Differentiation process Cell Size Cells Characteristics Collaborations Defect Deposition Diabetes Mellitus Disease Exhibits Extramural Activities Failure Fatty acid glycerol esters Filtration First Degree Relative Functional disorder Genes Goals Hyperplasia Hypertrophy Impairment Individual Inflammatory Insulin Insulin Resistance Interleukin-6 Lead Liver Metabolic Modeling Muscle Mutation National Institute of Diabetes and Digestive and Kidney Diseases Nature Non-Insulin-Dependent Diabetes Mellitus Nylons Obesity Organ Overweight Pancreas Paper Pathogenesis Peroxisome Proliferator-Activated Receptors Pilot Projects Pioglitazone Preparation Process Property Rattus Recording of previous events Recruitment Activity Reporting Resistance Risk Factors Role Tail Testing Time Work adipocyte differentiation adiponectin diabetic glucose uptake insulin sensitizing drugs lipid biosynthesis response rosiglitazone

项目摘要

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 were unable to find an association between the size of the large fat cells per se and 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. A reanalysis of these questions with a much larger group of subjects spanning a much wider range of BMI has confirmed the correlation between the proportion of small cells and IR but also showed a correlation between large cell size and IR. We attribute the failure to observe this in the earlier pilot study to the smallnumber of subjects the restricted range of BMI. A paper is in preparation. In collaboration with the Smith lab (Gothenburg) we have found a correlation between the size of the large cells and IR in a group of leaner, younger subjects who were first degree relatives of type 2 diabetics (paper in revision). 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. Considering these results together with those from the Stanford group (previous paragraph) and work in other sections of LBM, we conclude that large cell size is a primary risk factor for insulin resistance, along with an excess of small cells, reflecting 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. In collaboration with the McLaughlin lab (Stanford) we have also tested the hypothesis that small adipocytes per se are subject to impaired differentiation and function. Small adipocytes were isolated from epididymal adipose tissue of Zucker Obese (ZO) and Lean (ZL) rats and separated by sequential filtration through nylon meshes. Using quantitative real-time PCR for cell differentiation and inflammatory genes we found that the small cels represented a greater proportion in ZO than ZL rats. The small cells in the ZO rats had decreased adiponectin, and increased visfatin and IL-6 levels. The small adipocytes in the ZO rats also had lower adiponectin and PPARγ levels than in the ZL rats but increased IL-6. We thus confirmed for these animal models that the small adipocytes exhibited impaired cell differentiation and pro-inflammatory activity in addition to being present in higher proportions. We suggest that these properties contribute to insulin resistance in the animals. See Ref. # 1.

我们继续与Cushman Lab（NIDDK）和几个壁外实验室的合作，以分析脂肪组织中的细胞大小分布，以阐明脂肪细胞大小和胰岛素抵抗之间的关系。我们先前报道说，这种分布大致是双模型的，具有大型成熟细胞的高斯峰和小细胞的指数尾巴。与先前的假设相反，当适度的肥胖受试者的肥胖症相匹配时，我们找不到大脂肪细胞本身的大小与胰岛素抵抗（IR）之间的关联。相反，我们发现大细胞和IR的比例之间存在相关性，耐药受试者的大细胞不足。我们提出，这反映了脂肪细胞分化的损害，并导致脂肪储存能力不足和其他器官（例如肝脏，胰腺和肌肉）的异位脂肪沉积，这些器官无法很好地处理大量的脂肪。对这些问题的重新分析，跨越较大范围的BMI的受试者群体证实了小细胞和IR的比例之间的相关性，但也显示出大细胞大小与IR之间的相关性。我们将未在早期的试点研究中观察到这一点的人将其归因于BMI受限制范围的受试者的小numberber。一篇论文正在准备。在与史密斯实验室（哥德堡）合作的情况下，我们发现了一组较苗条的，年轻的受试者，它们是2型糖尿病患者的一级亲戚（修订版）。我们认为这是因为较瘦的受试者仍然能够扩展其脂肪细胞，而肥胖的受试者则达到了细胞膨胀的极限（肥大），并且必须募集新细胞（增生）。此外，施用胰岛素敏化药物（例如吡格列酮或罗格列酮）会导致新细胞的募集，从而增加了小细胞的比例，并扩大了现有大细胞的扩展（制备中的纸张）。因此，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历史。考虑到这些结果与Stanford组的结果（上一段），并在LBM的其他部分起作用，我们得出结论，大细胞大小是胰岛素抵抗的主要危险因素，以及过量的小细胞，反映了分化受损。实际上，这两个属性可能是相关的，因为可能会通过扩大其健康操作范围以外的现有脂肪细胞来补偿新脂肪细胞的潜在缺陷。与麦克劳克林实验室（斯坦福）合作，我们还检验了以下假设：小脂肪细胞本身会受到分化和功能受损的影响。从Zucker肥胖（ZO）和瘦（ZL）大鼠的附睾脂肪组织中分离出小的脂肪细胞，并通过尼龙网格通过顺序过滤分离。使用定量的实时PCR进行细胞分化和炎症基因，我们发现小碳在ZO中的比例比ZL大鼠更大。 ZO大鼠中的小细胞降低了脂联素，并增加了粘蛋白和IL-6水平。 ZO大鼠中的小脂肪细胞的脂联素和PPARγ水平也低于ZL大鼠，但IL-6增加。因此，我们证实了这些动物模型，小脂肪细胞除了以较高比例存在外，还表现出受损的细胞分化和促炎活性。我们建议这些特性有助于动物的胰岛素抵抗。参见参考。＃1。