What is it about?
We mapped the mechanism of action of the core circadian clock protein REVERBa in the liver. We found an extensive network of REVERBa regulated genes in the liver. However, a liver-specific knockout of the REVERBa gene caused a remarkably small impact on the liver, under conditions of alignment between the light-dark cycle, and feeding behaviour. However, if eating was mis-aligned to the light-dark cycle, mimicking the effect of eating late at night, we saw a massive effect in the liver lacking REVERBa. This identifies an unexpected role for the liver circadian clock as a buffer mechanism to smooth out the metabolic consequences of eating against the usual circadian routine. We think that with persistent mis-aligned feeding, eg longer-term night shift work, that this mechanism is over-whelmed, resulting in metabolic consequences.
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Why is it important?
We don't know why organs like the liver have an internal circadian clock. It was assumed that such a clock would control cycles of metabolic activity. However, we discovered that these cycles result from feeding behaviour, and do not rely on a clock in the liver. However, we did discover that the liver clock is important to buffer the effects of disrupted feeding rhythms.
Perspectives
It is striking how extensively REVERBa binds to the liver cell genomic DNA, potentially regulating many genes. Indeed, loss of the REVERBa genes in all tissues results in obesity, and massive adipose tissue expansion. However, loss of REVERBa in the liver had only a small effect. This suggested that REVERBa was poised to act, but needed a trigger. So, we tested misaligned feeding as a challenge, and here discovered that this revealed a critical role for REVERBa in limited the liver metabolic response to unexpected eating events.
david ray
University of Oxford
Read the Original
This page is a summary of: Nuclear receptor REVERBα is a state-dependent regulator of liver energy metabolism, Proceedings of the National Academy of Sciences, September 2020, Proceedings of the National Academy of Sciences,
DOI: 10.1073/pnas.2005330117.
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