Circadian rhythms are synchronized in mammals by time of feeding and light exposure. The mechanisms of circadian entrainment by external light stimuli are well established; however, the effects of feeding cues are unclear. Research published in Cell now shows that the feeding-associated hormones, insulin and insulin-like growth factor 1 (IGF1), act as global synchronizing cues for mammalian circadian rhythms.

Credit: Malte Mueller/Getty

“As biological circadian rhythms are a cellular property, non-proliferating fibroblast cells are the ideal system for investigating fundamental questions about clock mechanisms,” explains corresponding author John S. O’Neill. The authors observed that insulin treatment induced expression of the PERIOD clock protein PER2 in fibroblasts. “We saw the same effect in primary cells (cardiomyocytes and neurons), gut organoids and tissues ex vivo (lung and kidney),” says O’Neill. Importantly, insulin treatment in reporter mice elicited rapid increases in PER2 expression compared with control mice, implicating insulin as a circadian regulator in vivo.

Feeding cues were previously proposed to act on a hypothetical ‘food-entrainable oscillator’ (FEO), a neuronal locus that would translate environmental stimuli into behavioural changes. So far, research has failed to identify the FEO. By contrast, light stimuli are known to act through the hypothalamic suprachiasmatic nucleus (SCN). In the present study, the researchers found that the SCN did not respond to insulin treatment.

Interestingly, IGF1 was also found to induce PER2 expression in vitro. Moreover, PER2 expression could be induced in fibroblasts by insulin or IGF1 in the absence of glucose, suggesting that circadian entrainment is a new glucose-independent function of insulin signalling. In addition, pharmacological inhibition of insulin receptor and IGF1 receptor in reporter mice was associated with attenuated entrainment of circadian rhythms in response to changes in feeding time.

insulin and IGF1 are feeding cues that act systemically to synchronize circadian rhythms

“The final interesting finding is that the mechanism of PER2 induction involves increased translation of pre-existing mRNA, rather than transcriptional induction, with three-way coincidence detection being required to affect the molecular clockwork (that is, mTORC activation, PTEN inhibition and per-cognate microRNA degradation),” explains O’Neill. “We imagine this is important for allowing cells to discriminate timing signals from the large number of other signalling functions that are mediated by TOR complexes.”

These findings suggest that the FEO does not exist and that, instead, insulin and IGF1 are feeding cues that act systemically to synchronize circadian rhythms.