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Changes in the daily rhythm of lipid metabolism in the diabetic retina.

ABSTRACT: 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) ? exhibited rhythmic oscillation in retina and liver; PPAR? 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 PPAR? 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.

SUBMITTER: Wang Q

PROVIDER: S-EPMC3988159 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

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Changes in the daily rhythm of lipid metabolism in the diabetic retina.

Wang Qi Q Tikhonenko Maria M Bozack Svetlana N SN Lydic Todd A TA Yan Lily L Panchy Nicholas L NL McSorley Kelly M KM Faber Matthew S MS Yan Yuanqing Y Boulton Michael E ME Grant Maria B MB Busik Julia V JV

PloS one 20140415 4

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 (p ...[more]

PMID: 24736612

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Project description:Retinal function changes dramatically from day to night. Yet, clinical diagnosis, treatments, and experimental sampling occur during the day, leaving a significant gap in our understanding of the pathobiology occurring at night. While there is evidence that diabetes disrupts the circadian system that optimizes our physiology to the environmental light/dark cycle, the impact of such disruption is not well understood. This study investigates whether diabetes affects the retina's daily rhythm of gene expression to understand the pathobiology of diabetic retinopathy, a common complication of diabetes. Control and hyperglycemic littermate mice (Ins2Akita/J) were kept under a standard 12h:12h light/dark cycle until four months of age. Bulk mRNA sequencing was conducted in retinas collected every 4 hours throughout the 24 hr light/dark cycle. Computational approaches were used to detect rhythmicity, predict acrophase, identify differential rhythmic patterns, analyze phase set enrichment, and predict upstream regulators. The retinal transcriptome exhibited a tightly regulated rhythmic expression with a clear 12-hr axis of transcriptional rush, peaking at midday and midnight. The functions of day-peaking genes were enriched for DNA repair, RNA splicing, and ribosomal protein synthesis, whereas night-peaking genes were enriched for metabolic processes and growth factor signaling. Although the 12-hr transcriptional axis is retained in the diabetic retina, it was phase advanced by approximately 1-3 hours with a wider distribution. Upstream regulator analysis for the genes that showed phase shifts identified oxygen sensing mechanisms and HIF1alpha as regulators, but not the circadian clock, which remained in phase to the light/dark cycle. We propose a model in which early in diabetes, the diabetic retina experiences a ‘jet lag’ caused by the entrained circadian clock and its output being in one phase and metabolic pathways related to neuronal dysfunction and hypoxia driving advancement of gene expression to a different phase. Further studies are now required to evaluate the chronic implications of such internal jet lag for development of diabetic retinopathy.

Dataset Information

Changes in the daily rhythm of lipid metabolism in the diabetic retina.

Publications

Changes in the daily rhythm of lipid metabolism in the diabetic retina.

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