Oxyntomodulin regulates resetting of the liver circadian clock by food.

Dominic Landgraf,Johanna L Barclay,Daniel J Drucker,Alexei Leliavski,Christiane E Koch,Henrik Oster,Anthony H Tsang

doi:10.7554/elife.06253

Dominic Landgraf, Johanna L Barclay + Show 5 more

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https://doi.org/10.7554/elife.06253

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Abstract

Circadian clocks coordinate 24-hr rhythms of behavior and physiology. In mammals, a master clock residing in the suprachiasmatic nucleus (SCN) is reset by the light-dark cycle, while timed food intake is a potent synchronizer of peripheral clocks such as the liver. Alterations in food intake rhythms can uncouple peripheral clocks from the SCN, resulting in internal desynchrony, which promotes obesity and metabolic disorders. Pancreas-derived hormones such as insulin and glucagon have been implicated in signaling mealtime to peripheral clocks. In this study, we identify a novel, more direct pathway of food-driven liver clock resetting involving oxyntomodulin (OXM). In mice, food intake stimulates OXM secretion from the gut, which resets liver transcription rhythms via induction of the core clock genes Per1 and 2. Inhibition of OXM signaling blocks food-mediated resetting of hepatocyte clocks. These data reveal a direct link between gastric filling with food and circadian rhythm phasing in metabolic tissues.

Highlights

Extended night or rotating shift work is associated with an elevated risk for developing cancer, cardiovascular disease, immune deficiency, mood disorders, and metabolic alterations (Rosenberg and Doghramji, 2011; Herichova, 2013)
glucagon-like peptide-1 (GLP-1), glucagon-like peptide-2 (GLP-2), and glicentin-related pancreatic polypeptide (GRPP) (0.5–450 nM) had no significant resetting effects on PER2::LUC phase compared to PBS-treatment (Figure 1B–D)
In consequence, eating during the normal rest phase leads to a state of internal circadian desynchrony which has been suggested to underlie metabolic deregulation under shiftwork conditions (Vollmers et al, 2009; Salgado-Delgado et al, 2010; Barclay et al, 2012)

Summary

Introduction

Extended night or rotating shift work is associated with an elevated risk for developing cancer, cardiovascular disease, immune deficiency, mood disorders, and metabolic alterations (Rosenberg and Doghramji, 2011; Herichova, 2013). One major factor believed to contribute to this adverse health impact of shift work is a disruption of endogenous circadian clocks by mistimed resetting stimuli, so called Zeitgebers, as a consequence of altered sleep/wake schedules. Most organisms have evolved internal timekeepers to anticipate the environmental changes brought about by the Earth’s rotation around its axis. In mammals, these so called circadian clocks are based on ubiquitously expressed cellular interlocking transcriptional–translational feedback loops (TTLs) of clock genes/ proteins (Albrecht, 2012). In the core TTL, the transcriptional activators circadian locomotor output cycles kaput (CLOCK) and brain and muscle ARNT-like 1 (BMAL1; ARNTL) regulate the expression of two Cryptochrome (Cry1/2) and three Period (Per1-3) genes. The clock machinery regulates physiology via orchestration of tissue-specific rhythmic expression of clock output genes (Yan et al, 2008)

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