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    • br Central control of GI ghrelin secretion The CNS

    2022-08-12


    Central control of GI ghrelin secretion The CNS communicates with the GI tract through the vagus nerve originating in the DMV and sympathetic spinal afferents emanating from the thoracic spinal chord (Bray, 2000). The cells that secrete peripheral ghrelin are under direct control of these two pathways. For example, subdiaphragmatic (SDA) lesions of the vagus nerve, or peripheral application of the cholinergic antagonist atropine, eliminate ghrelin release stimulated by caloric deprivation (Williams et al., 2003). These data suggest that cholinergic signaling controls peripheral release of ghrelin. Additional work on this topic indicates that intracisternal delivery TRH, a 3 amino dabigatran etexilate peptide produced in the hypothalamus, stimulates peripheral ghrelin release and food intake release in anesthetized rats (Ao et al., 2006). Importantly, this effect was abolished by cervical vagotomy indicating that hindbrain TRH signaling utilizes the vagus as a conduit to stimulate peripheral ghrelin. Sympathetic neurons originating from the spinal chord also contact GI tract and this signaling mechanism is important for thermogenesis, gastric motility, and gastric secretion. Electrical or chemical activation of sympathetic spinal neurons stimulate ghrelin release in anesthetized rats (Mundinger et al., 2006). It is unclear if this sympathetic connection is necessary for conditioned ghrelin release. Sympathetic neurons are also activated by environmental or metabolic stress. Notably, once released, ghrelin reduces HPA activity and depressive-like behaviors in stressed rodents (Lambert et al., 2011, Lutter et al., 2008, Spencer et al., 2012). Therefore sympathetic innervation of GI ghrelin cells could stimulate peripheral ghrelin release to regulate physiological responses to stress and/or feeding behavior. Interestingly, GI ghrelin cells display increased expression of circadian clock genes in rodents exposed to RFS (Silver et al., 2011), a phenomenon correlated with peripheral ghrelin release. Recent data on this topic indicate that genetic ablation of the clock gene, BMAL1, attenuates RFS induced increases in food intake and peripheral ghrelin release (Laermans et al., 2015). These data raise the possibility that descending projections from the hindbrain and spinal chord may program GI cells to release ghrelin once learning has occurred. In this way, circadian entrainment of GI ghrelin cells may maintain pre-conditioned ghrelin release in the absence of CNS input.
    Peripheral control of GI ghrelin secretion Ghrelin is produced from X/A-like oxytinic cells in rats and P/D1 cells in humans (Müller et al., 2015). These cells represent the second most abundant endocrine cell type present in the gastrointestinal tract. X/A-like cells are most abundant in the gastric body of the fundus relative to the small intestines (Laermans et al., 2015). X/A-like cells are also present in the large intestines where they are in direct contact with the lumen as opposed to gastric X/A-like cells that are not (Sakata et al., 2002). The functional relevance of X/A-like cells is demonstrated by reduced ghrelin secretion following gastrectomy (Jeon et al., 2004). Fasting leads to increased mRNA expression of ghrelin and decreased ghrelin peptide content in X/A-like cells (Toshinai et al., 2001). This evidence indicates that during fasting X/A-like cells produce more ghrelin and subsequently release it into circulation. In contrast circulating ghrelin levels decrease in conditions of excess body weight and obesity (Tschöp et al., 2000). Several metabolic factors, including GI peptides control ghrelin secretion from X/A-like cells. For a more detailed review the reader is directed to (Stengel and Taché, 2012). Perhaps not surprisingly, GI peptides both stimulate and decrease ghrelin secretion in effort to maintain stable energy homeostasis. In these experiments both in vitro use of ghrelinoma MGN 3-1 cells and in vivo rodent experiments have been employed (Ao et al., 2006, Hosoda and Kangawa, 2008). Somatostatin or growth hormone-inhibiting hormone (GHIH) inhibits ghrelin secretion through a somatostain-2 receptor mediated mechanism in both X/A-like and P/D1 cells (Shimada et al., 2003, Iwakura et al., 2011). X/A ghrelin secretion is also inhibited by glucagon-like peptide-1 (GLP-1) in both rats and humans (Hagemann et al., 2007, Pérez-Tilve et al., 2007). However these results were not confirmed in rat or in vitro studies conducted in separate laboratories (Mundinger et al., 2006, Hosoda and Kangawa, 2008). Both insulin (Iwakura et al., 2011, Saad et al., 2002) and CCK-8 (Brennan et al., 2007) also have reported inhibitory effects on ghrelin secretion. Inhibition of ghrelin secretion has also been observed following administration of gastrin releasing peptide in rats (de la Cour et al., 2007).