Dissociation between diurnal cycles in locomotor activity, feeding behavior and hepatic PERIOD2 expression in chronic alcohol-fed mice

Abstract

Chronic alcohol consumption contributes to fatty liver disease. Our studies revealed that the hepatic circadian clock is disturbed in alcohol-induced hepatic steatosis, and effects of chronic alcohol administration upon the clock itself may contribute to steatosis. We extended these findings to explore the effects of chronic alcohol treatment on daily feeding and locomotor activity patterns. Mice were chronically pair-fed ad libitum for 4 weeks using the Lieber-DeCarli liquid diet, with calorie-controlled liquid and standard chow diets as control groups. Locomotor activity, feeding activity, and real-time bioluminescence recording of PERIOD2::LUCIFERASE expression in tissue explants were measured. Mice on liquid control and chow diets exhibited normal profiles of locomotor activity, with a ratio of 22:78% day/night activity and a peak during early night. This pattern was dramatically altered in alcohol-fed mice, marked by a 49:51% ratio and the absence of a distinct peak. While chow-diet fed mice had a normal 24:76% ratio of feeding activity, with a peak in the early night, this pattern was dramatically altered in both liquid-diet groups: mice had a 43:57% ratio, and an absence of a distinct peak. Temporal differences were also observed between the two liquid-diet groups during late day. Cosinor analysis revealed a ~4-h and ~6-h shift in the alcohol-fed group feeding and locomotor activity rhythms, respectively. Analysis of hepatic PER2 expression revealed that the molecular clock in alcohol-fed and control liquid-diet mice was shifted by ~11 h and ~6 h, respectively. No differences were observed in suprachiasmatic nucleus explants, suggesting that changes in circadian phase in the liver were generated independently from the central clock. These results suggest that chronic alcohol consumption and a liquid diet can differentially modulate the daily rhythmicity of locomotor and feeding behaviors, aspects that might contribute to disturbances in the circadian timing system and development of hepatic steatosis.

Distinct metabolic adaptation of liver circadian pathways to acute and chronic patterns of alcohol intake

“…Specifically, diurnal locomotor rhythmicity became significantly dampened after switching to ethanol feeding, concurrent with a significant decrease (2.5 times) of nighttime activity and a slight increase of daytime activity in chronic EtOH mice ( Fig. 1 H-K), in agreement with a previous study (18). Of note, liquid diet was replaced daily at zeitgeber time 10 (ZT10) to ZT12 in the current study, and we observed a small bout of locomotor activity during the food refill, most likely because of experimental intervention ( Fig.…”

Neural Mechanisms of Circadian Regulation of Natural and Drug Reward

“…For example, repeated amphetamine administration increases daytime locomotor activity in adolescent female rats [ 17 ]. Chronic alcohol exposure also increases daytime locomotor activity in mice, eliminating the typical rhythm as well as the peak in activity during the early night [ 79 ]. Over time, drugs of abuse also cause a loss of rhythmicity in self-administration and drug intake.…”

Inhibition of expression of the circadian clock gene Period causes metabolic abnormalities including repression of glycometabolism in Bombyx mori cells

“…Changes in the alcohol metabolic pathway were observed in a Drosophila Per mutant, resulting in differences in alcohol tolerance and clearance capability64. On the other hand, long-term alcohol intake in mice can lead to changes in the circadian rhythm65, whilst damaging the normal rhythm of liver glycogen metabolism66. Numerous studies have reported such reciprocal regulation of the circadian clock by metabolites, whereby the metabolites regulate expression of core circadian clock genes, thus changing the circadian rhythm.…”