Expression of circadian genes in subcutaneous adipose tissue of obese men with glucose intolerance and type 2 diabetes

D. Minchenko
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引用次数: 2

Abstract

Objective: Accumulating evidence raises the hypothesis that dysregulation of intrinsic clock mechanisms which control the main metabolic processes are involved in the development of the most profound public health problems: obesity, metabolic syndrome and type 2 diabetes. We sought therefore to identify the dysregulation of molecular components of circadian clock in subcutaneous adipose tissue of obese men with impaired glucose tolerance and type 2 diabetes. Methods: We investigated the expression of key circadian genes by quantitative polymerase chain reaction (qPCR) in subcutaneous adipose tissue from 24 adult males divided into four equal groups: lean controls and obese men with normal glucose tolerance (NGT), impaired glucose tolerance (IGT) and type 2 diabetes. Results: The expression levels of circadian genes PER2, CLOCK, ARNTL/BMAL1 and CRY1 were decreased in subcutaneous adipose tissue of NGT obese men versus lean controls and these changes were negatively correlated with increased body mass index (BMI). At the same time, no significant changes were observed in PER1 gene expression in adipose tissue of this group of patients. In subcutaneous adipose tissue of IGT obese cases we found decreased levels of PER1, CLOCK and ARNTL/BMAL1 gene expressions compared to NGT obese individuals. Moreover, the expression levels of CLOCK, PER2 and CRY1 genes were down-regulated in subcutaneous adipose tissue of obese men with type 2 diabetes versus IGT obese patients; however, ARNTL/BMAL1 gene expression was up-regulated. Conclusions: Our data demonstrate that suppression of most circadian gene expressions in subcutaneous adipose tissue of obese men with NGT is negatively correlated with increased BMI and can contribute to the development of obesity. The decreased expression of PER1 gene as well as an additional suppression of ARNTL/BMAL1 and CLOCK gene expressions in subcutaneous adipose tissue of obese men with glucose intolerance is associated with insulin resistance and IGT. At the same time, development of type 2 diabetes in obese men correlates with suppression of CLOCK, PER2, and CRY1 gene expressions. These results demonstrate that obesity and its complications differentially suppress clock gene expressions in subcutaneous adipose tissue, rendering this pathway as a potential therapeutic target.
糖耐受不良和2型糖尿病的肥胖男性皮下脂肪组织中昼夜节律基因的表达
目的:越来越多的证据提出了这样一种假设,即控制主要代谢过程的内在时钟机制失调参与了最深刻的公共卫生问题的发展:肥胖、代谢综合征和2型糖尿病。因此,我们试图确定患有糖耐量受损和2型糖尿病的肥胖男性皮下脂肪组织中生物钟分子成分的失调。方法:采用定量聚合酶链反应(qPCR)技术,研究了24名成年男性皮下脂肪组织中关键昼夜节律基因的表达,这些男性被分为四组:正常糖耐量(NGT)、糖耐量受损(IGT)和2型糖尿病的消瘦对照组和肥胖组。结果:NGT肥胖男性皮下脂肪组织中昼夜节律基因PER2、CLOCK、ARNTL/BMAL1和CRY1的表达水平较瘦对照组降低,且这些变化与体重指数(BMI)的增加呈负相关。同时,本组患者脂肪组织中PER1基因表达未见明显变化。在IGT肥胖患者的皮下脂肪组织中,我们发现与NGT肥胖个体相比,PER1、CLOCK和ARNTL/BMAL1基因表达水平降低。与IGT肥胖患者相比,肥胖2型糖尿病男性皮下脂肪组织中CLOCK、PER2和CRY1基因表达水平下调;而ARNTL/BMAL1基因表达上调。结论:我们的数据表明,NGT肥胖男性皮下脂肪组织中大多数昼夜节律基因表达的抑制与BMI升高呈负相关,并可能促进肥胖的发展。在患有葡萄糖耐受不良的肥胖男性皮下脂肪组织中,PER1基因表达的降低以及ARNTL/BMAL1和CLOCK基因表达的额外抑制与胰岛素抵抗和IGT有关。同时,肥胖男性2型糖尿病的发生与CLOCK、PER2和CRY1基因表达的抑制有关。这些结果表明,肥胖及其并发症在不同程度上抑制了皮下脂肪组织中的时钟基因表达,使这一途径成为潜在的治疗靶点。
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