Chronic jetlag-induced alterations in pancreatic diurnal gene expression

Abstract

Cell-autonomous circadian clocks exist in nearly every organ and function to maintain homeostasis through a complex series of transcriptional-translational feedback loops. The response of these peripheral clocks to external perturbations, such as chronic jetlag and shiftwork, has been extensively investigated. However, an evaluation of the effects of chronic jetlag on the mouse pancreatic transcriptome is still lacking. Herein we report an evaluation of the diurnal variations encountered in the pancreatic transcriptome following exposure to an established chronic jetlag protocol. We found approximately 5.4% of the pancreatic transcriptome was rhythmic. Following chronic jetlag, we found the number of rhythmic transcripts decreased to approximately 3.6% of the transcriptome. Analysis of the core clock genes, which orchestrate circadian physiology, revealed that nearly all exhibited a shift in the timing of peak gene expression - known as a phase shift. Similarly, over 95% of the rhythmically expressed genes in the pancreatic transcriptome exhibited a phase shift, many of which were found to be important for metabolism. Evaluation of the genes involved in pancreatic exocrine secretion and insulin signaling revealed many pancreas-specific genes were also rhythmically expressed and several displayed a concomitant phase shift with chronic jetlag. Phase differences were found 9 days after normalization, indicating a persistent failure to reentrain to the new light-dark cycle. This study is the first to evaluate the endogenous pancreatic clock and rhythmic gene expression in whole pancreas over 48 hours, and how the external perturbation of chronic jetlag affects the rhythmic expression of genes in the pancreatic

Chronic Jetlag Alters the Landscape of the Pancreatic Lipidome

“…In prior transcriptomic experiments investigating the effects of CJ on the pancreas, we observed that the core clock genes remained robustly rhythmic despite perturbations in the LD cycle. However, we found that there was a consistent, approximately 4-hour, phase shift of nearly all the core clock genes 14 . This translated to shifts in the phase of genes for many pathways important for lipid metabolism.…”

“…13 Our laboratory recently carried out a whole-pancreas transcriptomic evaluation of WT mice subjected to 1 month of a chronic jetlag (CJ) protocol that mimics human shiftwork. 14 During our evaluation, we found that transcriptomic signatures corresponding to multiple lipid metabolism-related pathways were preferentially phase shifted (ie, shift in the timing of peak 24-hour expression). These novel data prompted us to understand the downstream effects on the pancreatic cellular lipid content, yet no study that evaluates the pancreatic lipidome exists.…”

“…At 9 months of age, all mice were shifted back to standard lighting conditions 12 hours before the first time point. 14 Twelve mice (6 males/6 females) were then killed every 4 hours for 24 hours starting at zeitgeber time 0 (ZT0; 0600 hours = first time point). The pancreata were dissected and snap frozen in liquid nitrogen until lipid extraction was performed.…”

Chronic Jetlag Accelerates Pancreatic Neoplasia in ConditionalKras-Mutant Mice

“…5,6,26,27 To further evaluate the role of clock dysfunction in PDAC development, we subjected mice to a wellcharacterized chronic jetlag (CJ) protocol. 9,25 Interestingly, in KC mice prone to PDAC formation, we found that CJ promoted an increase in FI/PanIN development leading to more advanced lesions. 10 We then used a series of scRNAseq experiments to identify fibroblasts as the susceptible cell type to CJ within the developing PDAC tumor microenvironment.…”

“…Starting at 4-6 weeks of age, KC mice were subjected to either a normal circadian (NC) 12-hour light: dark (LD) cycle condition, or a chronic jetlag protocol (CJ) known to mimic altered sleep-wake cycles. 6,9 CJ consisted of a 12-hour LD cycle, phase-shifted forward 4 hours every 2-3 days. Mice were kept under their respective conditions until the study endpoint at 5 and 9 months of age.…”