Best Practice & Research Clinical Endocrinology & Metabolism
4Circadian clock-gastrointestinal peptide interaction in peripheral tissues and the brain
Introduction
To optimally adjust behavior, physiology, and metabolism to the 24-h rhythm of day and night and to anticipate daily recurring environmental changes, most organisms have evolved endogenous, so called circadian clocks. Although in mammals, the suprachiasmatic nucleus (SCN) in the hypothalamus is the master circadian pacemaker, most tissues, including other brain regions and organs of the digestive system, harbor self-sustained cellular circadian clocks [1]. Via the retina, the SCN is aligned with the light–dark cycle and coordinates all other oscillators throughout the body with external time. At the molecular level, circadian rhythms emerge from clock genes and proteins that form interconnected autoregulatory transcriptional-translational feedback loops (TTLs) [2].
In addition to maintaining TTL function, clock genes regulate large numbers of clock-controlled genes that are rhythmically expressed in an organ-specific manner. Food intake can alter the expression of clock and clock-controlled genes in metabolic tissues ∗[3], ∗[4], ∗[5], adapting digestive and metabolic rhythms to meal timing [6]. When food is restricted to the normal inactive phase, animals show food anticipatory activity (FAA). This behavioral entrainment by food is attributed to an unidentified clock network termed the food-entrainable oscillator (FEO) [7]. The SCN, however, is largely irresponsive to food which eventually leads to misalignment of peripheral and master clocks under mistimed feeding conditions. Animal experiments suggest that such desynchronization among internal oscillators can lead to obesity, diabetes, and even early death [8], [9], [10], [11]. In humans, studies with shift workers – who often eat at irregular times – suggest a higher prevalence of metabolic disorders [12], ∗[13], [14], [15]. Gastrointestinal (GI) hormones and their effects on circadian rhythms in different tissues may play an important role in this context.
Energy metabolism is regulated by interplay of the brain and peripheral organs. This connection is part of the conceptional gut–brain axis [16]. A complex system of central and peripheral signals, including GI peptides, regulates food intake, digestion, and energy storage. GI peptides are expressed in both, the brain and the GI tract. Many of them show circadian mRNA expression and secretion patterns or their receptors are expressed in a circadian fashion [17]. Numerous rhythmically expressed genes are coding for GI peptides, their precursors or receptors. This is expected when considering that secretion of most GI peptides is associated with food intake and digestion which, in turn, is directly or indirectly (via the sleep-wake rhythm) controlled by the circadian system [18]. Some of these oscillations, however, are retained in the absence of metabolic rhythms, e.g. in fasted animals, suggesting a more direct circadian control. In some cases, circadian control of secretion rhythms is inferior to food-dependent induction of secretion [19], [20].
To better understand the role of circadian misalignment in the pathology of metabolic disorders, it is essential to decipher the complex crosstalk between circadian clocks and GI peptides in the brain and in digestive organs. This review provides an overview about the role of GI peptides in adjusting central and peripheral circadian rhythms.
Section snippets
Interactions of gastrointestinal hormones and circadian clocks
Most GI hormones are secreted peripherally to organize the process of uptake and breakdown of nutrients in metabolic tissues. Some of them, however, are transported across the blood–brain barrier (BBB) to induce signals in hypothalamic areas. Despite their classification as gastrointestinal hormones, a few are even secreted in the brain itself acting as neurotransmitters. Besides their numerous functions in food processing, some GI peptides can influence circadian clock regulation in different
Summary
In this review, we outlined the reciprocal interaction between circadian clocks and GI peptides (Fig. 1). A clear distinction between clock and food intake as regulators of GI peptide secretion is often difficult. However, under normal conditions, i.e., when different Zeitgebers such as the light–dark cycle and food availability are aligned, it may not be critical whether rhythms of a particular hormone are driven by clock genes directly or by other time cues under circadian control. In
Acknowledgements
This work was supported grants of the German Research Foundation (SFB-134 & GRK-1957 (HO, AMN) & Emmy Noehter Program (DL)) and the Volkswagen Foundation (Lichtenberg Program (HO)). We thank Dr. Rita Barandas for critical comments on the manuscript.
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Contributed equally.