Orexins stimulate the ‘appetite’ of the gut (2011)

Orexins are a pair of peptides (Orexin A and orexin B; OXA and OXB) found in a small group of neurones in the perifornical and lateral hypothalamic area (LHA) of the brain, which was formerly implicated in the control of mammalian feeding behaviour (Willie et al. 2001). These peptides actually increase during fasting, and facilitate food consumption and wakefulness. There is accumulating evidence that orexins and their receptors are widely distributed outside the brain, including vagal and spinal nerves, and enteric plexus, mucous and musculature in the gut (Kirchgessner, 2002). This agrees well with the physiological point of view that appetite should reflect energy homeostasis in the whole body, and actions of numerous organs and tissues are coordinated to maintain the body's energy. It is well known that metabolic control occurs in gastric emptying, which is smoothly achieved by coordinating gastric and duodenal motor activity. Ingested water quickly passes through the stomach, while liquid meals containing nutrients are transferred to the duodenum at a rate of 1–4 kcal min−1 (Hunt & Stubbs, 1975). Digestion and absorption of nutrients are thus controlled by regulating antroduodenal transport. In a recent issue of The Journal of Physiology, Squecco et al. (2011) demonstrated that OXA potentiates mechanical and electrical activities in murine duodenal musculature. The continuation of these responses in the presence of tetrodotoxin (TTX) suggests a direct effect on the smooth muscle. This mechanism is likely to play a fundamental role in gastric emptying, since during fasting residual orexins presumably released from the enteric neurones and endocrine cells, including gastrin-releasing G-cells (Kirchgessner, 2002), maintain gastro-duodenal motor activity. After food intake, the stomach stores and slowly releases it into the small intestine with the support of duodenal motor activity, where orexins mediate excitation (stimulates the appetite of the gut), which remains inversely dependent on nutrient absorption (Fig. 1). Simple schematic diagram showing the interaction of orexins’ (OXs) effects For the regulation of acid secretion, the control of appetite can be classified into three phases: cephalic, gastric and intestinal. The cephalic and gastric phases are connected by oral food intake (feeding) supported by OX-mediated appetite in the brain (LHA), while the gastric and intestinal phases are connected by gastric emptying which is smoothly achieved by coordinated gastro-duodenal motions (gut appetite). OXs released from enteric neurons (EN) and endocrine cells (Endo: e.g. G-cells) enhance enteric motor neurone activity and smooth muscle contractility, whose underlying mechanisms have been elucidated by Squecco et al. (2011): enhancement of voltage-gated Ca2+ channels (VGCC), voltage-gated Na+ channels (VGSC) and the 2-APB-sensitive, store-operated Ca2+ channel (SOC)-like conductance; and suppression of K+ channels, including Ca2+-activated ones (KCa). The intestinal phase and cephalic phases are connected by nutrients absorbed and circulated. The three phases also communicate with each other through vagal efferent and afferent nerves. Squecco and colleagues first showed that in isolated duodenum segments, application of OXA potentiates spontaneous mechanical activity, and that nifedipine and 2-aminoethyl diphenyl borate (2-APB) largely suppress the excitatory actions of OXA. In parallel experiments, in order to assess underlying ionic mechanisms, electrical recordings were carried out in intact musculature preparations, i.e. without dissociation, in the current clamp and voltage clamp modes, respectively. In the latter series of electrical recordings, heptanol, a gap junction inhibitor, was added in extracellular medium to electrically isolate smooth muscle cells in the musculature. In line with the observed mechanical response, their current clamp experiments revealed that OXA evokes a transient large depolarization followed by a slow decay. Ionic substitutions and channel blockers indicated that several types of ionic channels were simultaneously modulated: enhancement of T- and L-type voltage-gated Ca2+ channels (VGCCs), voltage-gated Na+ channels (VGSCs) and the 2-APB-sensitive, store-operated Ca2+ channel (SOC)-like conductance; They also noted the suppression of K+ channels, including Ca2+-activated ones (KCa). This would systematically facilitate electrical excitability and intracellular Ca2+ activity in duodenal smooth muscle. It is now recognized that along with neurones and smooth muscle, pacemaking interstitial cells in the myenteric plexus are essential for gut motility and peristaltic motion. 2-APB also abolishes pacemaking Ca2+ oscillations in these interstitial cells (Nakayama et al. 2007), suggesting that orexins may coordinately enhance pacemaker activity. Voltage-clamp experiments by Squecco and colleagues next demonstrated that potentiation of VGSC and VGCC are accompanied by shifts of voltage dependency in the activation and inactivation kinetics. In the smooth muscle, L-type VGCCs are important in excitation–contraction coupling because these channels contribute to both Ca2+ entry and the generation of action potentials. The present finding of OXA potentiation of U-shaped inactivation suggests an increase in a non-inactivating second open state through an OXA receptor-linked pathway (Nakayama & Brading, 1993). Pathological alterations are likely to be associated with the orexin-mediated excitation. For instance, gut inflammation has been reported to suppress the voltage-dependent conversion of smooth muscle L-type VGCC into the second open state, accompanied by attenuation of tyrosine phosphorylation via src-kinase of this VGCC (Akbarali et al. 2010). Also, in light of orexins’ wide distribution in both the brain and gut, it is noteworthy that patients with inflammatory bowel disease (IBD) and irritable bowel syndrome (IBS) share some common symptoms and causes: especially, psychiatric stress affects the clinical course of both. Recent studies have revealed genetic associations in some subtypes of IBD and IBS (Camilleri et al. 2011). Collectively, the present findings on orexin-mediated excitatory mechanisms in the duodenum add unique knowledge to assess complex brain–gut interactions under physiological and pathological conditions. This work is supported by a grant from the Japan Gut Club.