Shift Work or Food Intake during the Rest Phase Promotes Metabolic Disruption and Desynchrony of Liver Genes in Male Rats

Abstract

In the liver, clock genes are proposed to drive metabolic rhythms. These gene rhythms are driven by the suprachiasmatic nucleus (SCN) mainly by food intake and via autonomic and hormonal pathways. Forced activity during the normal rest phase, induces also food intake, thus neglecting the signals of the SCN, leading to conflicting time signals to target tissues of the SCN. The present study explored in a rodent model of night-work the influence of food during the normal sleep period on the synchrony of gene expression between clock genes and metabolic genes in the liver. Male Wistar rats were exposed to forced activity for 8 h either during the rest phase (day) or during the active phase (night) by using a slow rotating wheel. In this shift work model food intake shifts spontaneously to the forced activity period, therefore the influence of food alone without induced activity was tested in other groups of animals that were fed ad libitum, or fed during their rest or active phase. Rats forced to be active and/or eating during their rest phase, inverted their daily peak of Per1, Bmal1 and Clock and lost the rhythm of Per2 in the liver, moreover NAMPT and metabolic genes such as Pparα lost their rhythm and thus their synchrony with clock genes. We conclude that shift work or food intake in the rest phase leads to desynchronization within the liver, characterized by misaligned temporal patterns of clock genes and metabolic genes. This may be the cause of the development of the metabolic syndrome and obesity in individuals engaged in shift work.

Endogenous circadian system and circadian misalignment impact glucose tolerance via separate mechanisms in humans

“…An endogenous circadian rhythm in circulating glucose and insulin levels has been detected in humans by using intensive protocols performed under constant conditions ("constant routine" protocols) or when the behavioral cycle influences are accounted for by evenly distributing them across the entire circadian cycle ("forced desynchrony" protocols) (4,(10)(11)(12)14). In addition, circadian misalignment-as occurs in shift workers-also leads to impaired glucose metabolism in rodents and humans (10,(25)(26)(27)(28)(29)(30)(31)(32).…”

Consequences of circadian dysregulation on metabolism

“…74 Forced activity during an 8-hour window of the inactive phase increases body mass, flattens glucose rhythms, alters glucose tolerance, shifts the peak in serum triglycerides to the daytime, and overall alters rhythmicity in the hypothalamus and the liver. [75][76][77] Nighttime food restriction in rats exposed to this forced activity protocol restores glucose rhythms and baseline body mass. 75 Approximately 20% of the global population works in night shifts, forcing individuals to be physically, mentally, and metabolically active out of circadian phase.…”

“…Restriction of feeding to the inactive phase, during the light phase in nocturnal rodents, increases body mass, fat mass, and liver clock gene profile. 75,76,94 When compounded with a high-fat diet, mice develop obesity, altered circadian endocrine, and locomotor profiles. 60,[95][96][97] Restricting high-fat diet consumption to the active phase, in contrast, can protect against reduced clock gene amplitude, weight gain, and metabolic disease.…”

Plasticity of circadian clocks and consequences for metabolism

“…Animal studies 6,8,54,130,131,16,132,133,134,135 6,48,49,50,7,52,8,53,54,55,56,57,58,59,60,5,130,133,135,136,137,138 Human experimental studies x 94,139,140,141,142,143,128 To study the effect of environmental conditions on the circadian clock and peripheral parameters, the animals have been exposed to constant light, dim light at night, aberrant light cycles or shift-work paradigms. The human studies referred to in this .…”