Circadian Rhythms: Feeding time
All forms of life have to be able to cope with changes in their environment, including daily cycles in temperature and light levels. As a result, organisms as diverse as bacteria and humans have evolved inbuilt timekeeping mechanisms that are capable of tracking the 24-hour day.
These so-called ‘circadian’ clocks enable organisms to anticipate changes that take place in their environment, and adapt their biology accordingly. In addition to tracking time, biological clocks must stay synchronized (or entrained) with the world around them. To achieve this, circadian clocks can be influenced or reset by environmental factors called ‘zeitgebers’ (from the German for ‘time-giver’). The daily cycle of light and dark is a dominant zeitgeber for most organisms, while periodic food availability represents another powerful zeitgeber. Now, in eLife, Henrik Oster and colleagues—including Dominic Landgraf and Anthony Tsang as joint first authors—report how a hormone released from the gut after eating can help the body to track changes in mealtimes (Landgraf et al., 2015).
Circadian clocks have a profound impact on mammalian biology, and virtually all aspects of our lives—from sleep-wake cycles to patterns of hormone release and energy metabolism—follow pronounced daily rhythms (Albrecht, 2012). In mammals, it is well established that the suprachiasmatic nucleus (or SCN) contains the body's master clock. Located in the brain, just above the optic nerves, the SCN clock receives information about environmental light levels directly from the eyes, which keeps it in sync with the external world.
Twenty years of research into circadian clockwork mean that we understand relatively well how changes in light adjust the timing of the SCN clock. The expression of specific ‘clock genes’, such as Per1 and Per2, within neurons of the SCN is increased in response to light. This means that the SCN clock can be advanced or delayed to ensure it remains in time with the prevailing light–dark cycle. However, it has also become clear that there are other circadian clocks in most of the cells and tissues in the body (Guilding and Piggins, 2007; Mohawk et al., 2012).
Under normal circumstances, this network of clocks is kept in synchrony by the master clock in the SCN; but it has been known for many decades that behavioural rhythms in laboratory rodents can be entrained by restricting access to food to certain times of the day. These food-entrained rhythms are not affected by the light–dark cycle, and they can persist in animals that have had their SCN destroyed. A set mealtime is now known to be a dominant zeitgeber for these peripheral tissue clocks (such as the clock in the liver), with the expression of the clock genes in these tissues become aligned to feeding time (Damiola et al., 2000). In contrast, the SCN clock remains locked to the light–dark cycle. It makes sense for tissue-specific clocks to be sensitive to food instead of light because the availability of food in nature may not always coincide with other environmental factors.
Unlike modulation of the SCN clock by light, it is unclear which signals convey information about feeding time to reset the circadian clock in the liver. Oster, Landgraf, Tsang and colleagues—who are based at the Max Planck Institute for Biophysical Chemistry, and the Universities of Lübeck and Toronto—report that a gut hormone called oxyntomodulin is one of these signals. Oxyntomodulin is a peptide hormone that is released from the gut in response to food intake, and has been suggested to be a potential drug target to combat obesity in humans (Druce and Bloom, 2006).
Landgraf, Tsang et al. started by screening around 200 peptide molecules that are known to be involved in appetite and the regulation of body weight to see if any could adjust the molecular clock of liver tissue. This in vitro screen identified two molecules: oxyntomodulin and glucagon. In particular, treatment with oxyntomodulin could shift the liver clock by several hours, either forward or back, depending on the time it was administered. Both of these characteristics suggest that oxyntomodulin serves to set the liver clock to feeding rhythms in living organisms.
So how does oxyntomodulin reset the liver clock? Somewhat unusually, this hormone can bind to two different types of receptor protein (namely GLP-1 receptors and glucagon receptors; Pocai, 2013). Further experiments confirmed that oxyntomodulin's liver resetting activity depends on it stimulating glucagon receptors (and not GLP-1 receptors). This stimulation leads to a transient increase in the expression of the Per1 clock gene in the liver cells, which involves a signalling cascade that is reminiscent of the light-induced responses of the SCN (Tischkau et al., 2003).
Mice that were given oxyntomodulin when they would normally be resting showed an increase in Per expression in the liver, and experienced a shift in the timing of their liver clock. Treatment with oxyntomodulin also delayed and/or reduced the expression of genes involved in carbohydrate metabolism. However, treating the mice with oxyntomodulin during the period when they were normally active had no effect on the liver. Thus, oxyntomodulin's effects on the liver clock only occur at times of the daily cycle when the mice do not typically eat. Furthermore, oxyntomodulin had no effect the SCN master clock.
These experiments only demonstrate that artificially elevated levels of oxyntomodulin alter liver activity, so Landgraf, Tsang et al. then explored whether a mouse's normal levels of oxyntomodulin act to regulate its liver clock. When fasted animals were then given the opportunity to eat, oxyntomodulin levels in the blood increased within 20 minutes, and remained high for one hour. This signal was enough to alter clock gene activity in the liver. Landgraf, Tsang et al. then treated mice with antibodies that bind to oxyntomodulin. This treatment neutralized the hormone circulating in the body, and prevented its action, which weakened the resetting of the liver clock following food intake.
Landgraf, Tsang et al. suggest that the oxynto-modulin released by the gut following a meal serves as a timing cue for the liver clock. When food intake occurs at the expected times of day, the liver clock is relatively blind to this signal. However, when a meal occurs outside of a normal feeding time, the induced rise in oxyntomodulin serves to adjust the clock to a new feeding schedule. In this way, oxyntomodulin may function as an important signal that translates feeding time into the timing of an internal clock.
It will be important to examine oxyntomodulin signalling in situations were food is limited, and to explore whether it can also shift the clocks in other peripheral tissues, such as muscles and the pancreas. Furthermore, the therapeutic potential of this peptide hormone in correcting problems associated with ‘jet-lag’ and rapid travel through multiple time zones also awaits investigation.
References
-
Oxyntomodulin: a novel potential treatment for obesityTreatments in Endocrinology 5:265–272.https://doi.org/10.2165/00024677-200605050-00001
-
Challenging the omnipotence of the suprachiasmatic circadian timekeeper: are circadian oscillators present throughout the mammalian brain?European Journal of Neuroscience 25:229–255.
-
Central and peripheral circadian clocks in mammalsAnnual Review of Neuroscience 35:445–462.https://doi.org/10.1146/annurev-neuro-060909-153128
-
Action and therapeutic potential of oxyntomodulinMolecular Metabolism 3:241–251.https://doi.org/10.1016/j.molmet.2013.12.001
Article and author information
Author details
Publication history
Copyright
© 2015, Piggins and Bechtold
This article is distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use and redistribution provided that the original author and source are credited.
Metrics
-
- 2,259
- views
-
- 190
- downloads
-
- 3
- citations
Views, downloads and citations are aggregated across all versions of this paper published by eLife.
Download links
Downloads (link to download the article as PDF)
Open citations (links to open the citations from this article in various online reference manager services)
Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)
Further reading
-
- Biochemistry and Chemical Biology
- Microbiology and Infectious Disease
Malaria parasites have evolved unusual metabolic adaptations that specialize them for growth within heme-rich human erythrocytes. During blood-stage infection, Plasmodium falciparum parasites internalize and digest abundant host hemoglobin within the digestive vacuole. This massive catabolic process generates copious free heme, most of which is biomineralized into inert hemozoin. Parasites also express a divergent heme oxygenase (HO)-like protein (PfHO) that lacks key active-site residues and has lost canonical HO activity. The cellular role of this unusual protein that underpins its retention by parasites has been unknown. To unravel PfHO function, we first determined a 2.8 Å-resolution X-ray structure that revealed a highly α-helical fold indicative of distant HO homology. Localization studies unveiled PfHO targeting to the apicoplast organelle, where it is imported and undergoes N-terminal processing but retains most of the electropositive transit peptide. We observed that conditional knockdown of PfHO was lethal to parasites, which died from defective apicoplast biogenesis and impaired isoprenoid-precursor synthesis. Complementation and molecular-interaction studies revealed an essential role for the electropositive N-terminus of PfHO, which selectively associates with the apicoplast genome and enzymes involved in nucleic acid metabolism and gene expression. PfHO knockdown resulted in a specific deficiency in levels of apicoplast-encoded RNA but not DNA. These studies reveal an essential function for PfHO in apicoplast maintenance and suggest that Plasmodium repurposed the conserved HO scaffold from its canonical heme-degrading function in the ancestral chloroplast to fulfill a critical adaptive role in organelle gene expression.
-
- Biochemistry and Chemical Biology
- Cell Biology
Activation of the Wnt/β-catenin pathway crucially depends on the polymerization of dishevelled 2 (DVL2) into biomolecular condensates. However, given the low affinity of known DVL2 self-interaction sites and its low cellular concentration, it is unclear how polymers can form. Here, we detect oligomeric DVL2 complexes at endogenous protein levels in human cell lines, using a biochemical ultracentrifugation assay. We identify a low-complexity region (LCR4) in the C-terminus whose deletion and fusion decreased and increased the complexes, respectively. Notably, LCR4-induced complexes correlated with the formation of microscopically visible multimeric condensates. Adjacent to LCR4, we mapped a conserved domain (CD2) promoting condensates only. Molecularly, LCR4 and CD2 mediated DVL2 self-interaction via aggregating residues and phenylalanine stickers, respectively. Point mutations inactivating these interaction sites impaired Wnt pathway activation by DVL2. Our study discovers DVL2 complexes with functional importance for Wnt/β-catenin signaling. Moreover, we provide evidence that DVL2 condensates form in two steps by pre-oligomerization via high-affinity interaction sites, such as LCR4, and subsequent condensation via low-affinity interaction sites, such as CD2.