Location, location, location: important for jet-lagged circadian loops

Abstract

It is now believed that frequent jet lag or shifts of daily rhythms caused by rotating shift work can lead to deleterious health outcomes. Indeed, many serious health problems, including breast cancer, stroke, and cardiovascular disease, have been linked to an occupational history of shift work. This has heightened interest in better understanding the biological responses to jet lag and shift work, with the hope that this will pave the way to developing compounds that can help people avoid their negative health consequences. In this context, a report in this issue of the JCI takes us to a new level of understanding of the molecular control of the resetting of the multitude of internal biological clocks disrupted in a mouse model of jet lag.

Figure 1. An interconnected network of genes and gene products underlies circadian rhythm generation in the mammalian SCN cell.

The proteins CLK and ARNTL act by activating transcription and driving the expression of a number of genes. The products of these genes, including PER1, PER2, CRY1, and CRY2, provide a negative feedback signal to inhibit the activational drive of CLK and ARNTL. Several other genes also have feedback roles; for example, the genes encoding NR1D1 and RORα mediate a feedback loop to provide rhythmic inhibitory and activating drive, respectively, to the gene encoding ARNTL. Because Dbp is sensitive to the rhythmic transcriptional activation of CLK and ARNTL, DBP can act as a transcriptional activator for other, downstream genes.

Figure 2. Cellular clock genes adjust to new time zones at different rates in different body organs.

(A) In the central brain clock, the SCN, Per1 and Per2 lead the system in shifting. (B) Conversely, in the pancreas, Nr1d1 appears to take the lead. (C) The liver circadian clock shows an intermediate pattern. Red indicates genes slower to adjust to jet lag, and green denotes genes faster to respond, as indicated by Kiessling et al. (16).