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

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.