Department of Physiology, Michigan State University, East Lansing, Michigan, United States of America.
Department of Microbiology and Molecular Genetics, Michigan State University, East Lansing, Michigan, United States of America.
PLoS One. 2014 Apr 15;9(4):e95028. doi: 10.1371/journal.pone.0095028. eCollection 2014.
Disruption of circadian regulation was recently shown to cause diabetes and metabolic disease. We have previously demonstrated that retinal lipid metabolism contributed to the development of diabetic retinopathy. The goal of this study was to determine the effect of diabetes on circadian regulation of clock genes and lipid metabolism genes in the retina and retinal endothelial cells (REC). Diabetes had a pronounced inhibitory effect on the negative clock arm with lower amplitude of the period (per) 1 in the retina; lower amplitude and a phase shift of per2 in the liver; and a loss of cryptochrome (cry) 2 rhythmic pattern in suprachiasmatic nucleus (SCN). The positive clock arm was increased by diabetes with higher amplitude of circadian locomotor output cycles kaput (CLOCK) and brain and muscle aryl-hydrocarbon receptor nuclear translocator-like 1 (bmal1) and phase shift in bmal1 rhythmic oscillations in the retina; and higher bmal1 amplitude in the SCN. Peroxisome proliferator-activated receptor (PPAR) α exhibited rhythmic oscillation in retina and liver; PPARγ had lower amplitude in diabetic liver; sterol regulatory element-binding protein (srebp) 1c had higher amplitude in the retina but lower in the liver in STZ- induced diabetic animals. Both of Elongase (Elovl) 2 and Elovl4 had a rhythmic oscillation pattern in the control retina. Diabetic retinas lost Elovl4 rhythmic oscillation and had lower amplitude of Elovl2 oscillations. In line with the in vivo data, circadian expression levels of CLOCK, bmal1 and srebp1c had higher amplitude in rat REC (rREC) isolated from diabetic rats compared with control rats, while PPARγ and Elovl2 had lower amplitude in diabetic rREC. In conclusion, diabetes causes dysregulation of circadian expression of clock genes and the genes controlling lipid metabolism in the retina with potential implications for the development of diabetic retinopathy.
昼夜节律调节的破坏最近被证明会导致糖尿病和代谢疾病。我们之前已经证明，视网膜脂质代谢有助于糖尿病性视网膜病变的发展。本研究的目的是确定糖尿病对视网膜和视网膜内皮细胞（REC）中时钟基因和脂质代谢基因昼夜节律调节的影响。糖尿病对负时钟臂有明显的抑制作用，导致视网膜中 per1 的振幅降低；肝脏中 per2 的振幅降低和相位偏移；以及视交叉上核（SCN）中 cry2 节律模式的丧失。糖尿病使正时钟臂增加，表现为昼夜节律运动输出周期 kaput（CLOCK）和脑和肌肉芳香烃受体核转位样 1（bmal1）的振幅增加，以及视网膜中 bmal1 节律振荡的相位偏移；以及 SCN 中 bmal1 的振幅增加。过氧化物酶体增殖物激活受体（PPAR）α在视网膜和肝脏中表现出节律性振荡；糖尿病肝脏中 PPARγ 的振幅降低；固醇调节元件结合蛋白（srebp）1c 在 STZ 诱导的糖尿病动物视网膜中的振幅较高，但在肝脏中的振幅较低。延长酶（Elovl）2 和 Elovl4 在对照视网膜中均表现出节律性振荡模式。糖尿病视网膜失去了 Elovl4 的节律性振荡，Elovl2 的振荡幅度降低。与体内数据一致，从糖尿病大鼠中分离出的大鼠 REC（rREC）中 CLOCK、bmal1 和 srebp1c 的昼夜节律表达水平振幅较高，而 PPARγ 和 Elovl2 的振幅较低。总之，糖尿病导致视网膜中时钟基因和控制脂质代谢的基因昼夜节律表达失调，这可能对糖尿病性视网膜病变的发展有影响。
