Department of Endocrinology and Metabolism, Amsterdam UMC, location AMC, University of Amsterdam, room F5-162, P.O. Box 22660, 1100 DD, Amsterdam, the Netherlands.
Bioinformatics Laboratory, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands.
Diabetologia. 2019 Apr;62(4):704-716. doi: 10.1007/s00125-019-4813-5. Epub 2019 Feb 9.
AIMS/HYPOTHESIS: Animal studies have indicated that disturbed diurnal rhythms of clock gene expression in adipose tissue can induce obesity and type 2 diabetes. The importance of the circadian timing system for energy metabolism is well established, but little is known about the diurnal regulation of (clock) gene expression in obese individuals with type 2 diabetes. In this study we aimed to identify key disturbances in the diurnal rhythms of the white adipose tissue transcriptome in obese individuals with type 2 diabetes.
In a case-control design, we included six obese individuals with type 2 diabetes and six healthy, lean control individuals. All participants were provided with three identical meals per day for 3 days at zeitgeber time (ZT, with ZT 0:00 representing the time of lights on) 0:30, 6:00 and 11:30. Four sequential subcutaneous abdominal adipose tissue samples were obtained, on day 2 at ZT 15:30, and on day 3 at ZT 0:15, ZT 5:45 and ZT 11:15. Gene expression was measured using RNA sequencing.
The core clock genes showed reduced amplitude oscillations in the individuals with type 2 diabetes compared with the healthy control individuals. Moreover, in individuals with type 2 diabetes, only 1.8% (303 genes) of 16,818 expressed genes showed significant diurnal rhythmicity, compared with 8.4% (1421 genes) in healthy control individuals. Enrichment analysis revealed a loss of rhythm in individuals with type 2 diabetes of canonical metabolic pathways involved in the regulation of lipolysis. Enrichment analysis of genes with an altered mesor in individuals with type 2 diabetes showed decreased activity of the translation initiating pathway 'EIF2 signaling'. Individuals with type 2 diabetes showed a reduced diurnal rhythm in postprandial glucose concentrations.
CONCLUSIONS/INTERPRETATION: Diurnal clock and metabolic gene expression rhythms are decreased in subcutaneous adipose tissue of obese individuals with type 2 diabetes compared with lean control participants. Future investigation is needed to explore potential treatment targets as identified by our study, including clock enhancement and induction of EIF2 signalling.
The raw sequencing data and supplementary files for rhythmic expression analysis and Ingenuity Pathway Analysis have been deposited in NCBI Gene Expression Omnibus (GEO series accession number GSE104674).
目的/假设：动物研究表明，脂肪组织中时钟基因表达的昼夜节律紊乱会导致肥胖和 2 型糖尿病。昼夜节律计时系统对能量代谢的重要性已得到充分证实，但对于 2 型糖尿病肥胖个体中（时钟）基因表达的昼夜调节知之甚少。在这项研究中，我们旨在确定 2 型糖尿病肥胖个体白色脂肪组织转录组昼夜节律的关键变化。
采用病例对照设计，纳入 6 例 2 型糖尿病肥胖患者和 6 例健康瘦对照者。所有参与者在 zeitgeber 时间（ZT，ZT 0:00 代表开灯时间）0:30、6:00 和 11:30 每天提供 3 餐，共 3 天。在第 2 天的 ZT 15:30 和第 3 天的 ZT 0:15、ZT 5:45 和 ZT 11:15，连续采集 4 个皮下腹部脂肪组织样本。使用 RNA 测序测量基因表达。
与健康对照组相比，2 型糖尿病患者的核心时钟基因振幅振荡降低。此外，在 2 型糖尿病患者中，只有 1.8%（303 个基因）的 16818 个表达基因表现出明显的昼夜节律性，而健康对照组为 8.4%（1421 个基因）。富集分析显示，2 型糖尿病患者中与脂肪分解调节相关的经典代谢途径的节律性丧失。2 型糖尿病患者中变化的中值基因的富集分析显示，翻译起始途径“EIF2 信号”的活性降低。2 型糖尿病患者餐后血糖的昼夜节律降低。
结论/解释：与瘦对照组相比，肥胖 2 型糖尿病患者的皮下脂肪组织中昼夜时钟和代谢基因表达节律降低。需要进一步研究以探索我们研究中确定的潜在治疗靶点，包括时钟增强和 EIF2 信号诱导。
节律表达分析和 Ingenuity Pathway Analysis 的原始测序数据和补充文件已存入 NCBI Gene Expression Omnibus（GEO 系列注册号 GSE104674）。
