Metabolic and hormonal consequences of circadian rhythm disruption in Bmal1 null mice
D. Kennaway, M. Boden & T. Varcoe
There is compelling evidence that shiftworkers are at risk of developing metabolic disturbances, diabetes and obesity as a result of disruption to circadian rhythms, but the mechanisms by which this may occur are not clear. The Bmal1 null mouse, which lacks both central and peripheral tissue rhythms, was used in this study to address the role of circadian rhythmicity in metabolic homeostasis.
Male Bmal1 null mice and wild-type litter mates (2 months) were killed 4 hourly over 24 h and blood, liver and adipose tissue collected. Separate groups were subjected to glucose, pyruvate and insulin tolerance tests. Male and female Bmal1 null mice fed a 22% fat (w/w) diet were killed at 2 months and blood and tissues collected.
Across 24 h plasma insulin was lower and adiponectin and leptin were higher in Bmal1 null mice compared to wild-type mice while glucose and NEFA were unchanged. Liver pfkfb3 mRNA in Bmal1 null mice was decreased, but expression of per2, gck, pck1 and adipor2 mRNA was unchanged and the rhythm of per2, gck, and pfkfb3 mRNA absent. In adipose tissue, per2, adipoq, retn and nampt mRNA expression was decreased in Bmal1 null mice and the rhythm of expression of per2, adipoq and nampt mRNA absent.
Bmal1 null mice had normal glucose and insulin tolerance, but both male and female Bmal1 null mice had improved pyruvate sensitivity. Bmal1 mice of both sexes weighed less than wild type mice, but had larger epigonadal and retroperitoneal fat depots, although they responded similarly to the high fat diet with respect to increased adiposity and hormone changes.
These studies provide further evidence for a role of circadian rhythmicity in the glucose/insulin and adipoinsular axes. Disruption of tissue rhythmicity in shiftwork, in conjunction with poor diet and sleep loss may contribute to the health burden experienced by shiftworkers.
Declaration of interest: The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research project.
Funding: This work was supported, however funding details unavailable.