Chronodisruption by chronic jetlag impacts metabolic and gastrointestinal homeostasis in male mice

Abstract

Aim: Chronodisruption desynchronizes peripheral clocks and leads to metabolic diseases. Feeding cues are important synchronizers of peripheral clocks and influence rhythmic oscillations in intestinal microbiota and their metabolites. We investigated whether chronic jetlag, mimicking frequent time zone travelling, affected the diurnal fluctuations in faecal short-chain fatty acid (SCFA) levels, that feed back to the gut clock to regulate rhythmicity in gut function. Methods: Rhythms in faecal SCFAs levels and in the expression of clock genes and epithelial markers were measured in the colonic mucosa of control and jetlagged mice. The entraining effect of SCFAs on the rhythm in clock gene mRNA expression was studied in primary colonic crypts. The role of the circadian clock in epithelial marker expression was studied in Arntl −/− mice. Results: Chronic jetlag increased body weight gain and abolished the day/night food intake pattern which resulted in a phase-delay in the rhythm of faecal SCFAs that paralleled the shift in the expression of mucosal clock genes. This effect was mimicked by stimulation of primary colonic crypts from control mice with SCFAs. Jetlag abolished the rhythm in Tnfα, proglucagon and ghrelin expression but not in the expression of tight junction markers. Only a dampening in plasma glucagon-like peptide-1 but not in ghrelin levels was observed. Rhythms in ghrelin but not proglucagon mRNA expression were abolished in Arntl −/− mice. Conclusion:The altered food intake pattern during chronodisruption corresponds with the changes in rhythmicity of SCFA levels that entrain clock genes to affect rhythms in mRNA expression of gut epithelial markers.

Time-Restricted Feeding in Mice Prevents the Disruption of the Peripheral Circadian Clocks and Its Metabolic Impact during Chronic Jetlag

“…Several studies show that chronodisruption (genetic or environmental) disrupts the rhythms in food intake in mice [14,16,32]. This is in agreement with our results showing that the JL AL mice consumed equal amounts of calories during the day and night.…”

“…We previously showed that microbial metabolites such as SCFAs are known to entrain circadian clock gene expression in the colonic mucosa [16,42]. Therefore, circadian clock gene expression was studied in the mucosa of the distal colon over 24 h in Ctrl RF, JL AL, and JL RF mice.…”

“…We previously have shown that chronic jetlag in mice disturbed the rhythm in feeding patterns, which correlated with changes in the diurnal rhythms of microbial SCFA levels that affected gut clocks and downstream genes [16]. In the present study, we aim to investigate using an intervention with TRF during the induction of chronic jetlag whether food is an entraining factor during chronodisruption that (1) affects alterations in central clock genes; (2) triggers the food entrainable oscillator, ghrelin, in the stomach to stimulate food intake; (3) feeds back to the hypothalamus to prevent alterations in rhythmicity in Npy/Agrp expression; and (4) prevents the alterations in fecal SCFA levels induced by chronodisruption that, in turn, strengthen/resynchronize the rhythmic activation of the peripheral clock genes to promote health.…”

“…However, the suboptimal expression of circadian-driven genes compromises metabolic homeostasis. Studies in both humans and mouse models of chronodisruption (genetic or environmental) showed an increase in body mass, a loss in rhythmic physical activity, a dampening of the rhythmicity in the respiratory exchange ratio, glucose intolerance, and dyslipidemia [11][12][13][14][15][16]. Further, chronodisruption is also associated with diseases such as stroke, Alzheimer's disease, and breast and prostate cancer [11,[17][18][19][20][21].…”

“…Both in humans and mice, the intestinal microbiota and their metabolites display diurnal oscillations that are under influence of feeding rhythms [35][36][37]. Microbial metabolites such as short-chain fatty acids (SCFA) and bile acids are important entraining factors of peripheral clocks [16,38].…”