Ghrelin Indirectly Activates Hypophysiotropic CRF Neurons in Rodents

Laboratory of Neurophysiology, Multidisciplinary Institute of Cell Biology, Argentine Research Council (CONICET) and Scientific Research Commission, Province of Buenos Aires (CIC-PBA), La Plata, Buenos Aires, Argentina.
PLoS ONE (Impact Factor: 3.23). 02/2012; 7(2):e31462. DOI: 10.1371/journal.pone.0031462
Source: PubMed


Ghrelin is a stomach-derived hormone that regulates food intake and neuroendocrine function by acting on its receptor, GHSR (Growth Hormone Secretagogue Receptor). Recent evidence indicates that a key function of ghrelin is to signal stress to the brain. It has been suggested that one of the potential stress-related ghrelin targets is the CRF (Corticotropin-Releasing Factor)-producing neurons of the hypothalamic paraventricular nucleus, which secrete the CRF neuropeptide into the median eminence and activate the hypothalamic-pituitary-adrenal axis. However, the neural circuits that mediate the ghrelin-induced activation of this neuroendocrine axis are mostly uncharacterized. In the current study, we characterized in vivo the mechanism by which ghrelin activates the hypophysiotropic CRF neurons in mice. We found that peripheral or intra-cerebro-ventricular administration of ghrelin strongly activates c-fos--a marker of cellular activation--in CRF-producing neurons. Also, ghrelin activates CRF gene expression in the paraventricular nucleus of the hypothalamus and the hypothalamic-pituitary-adrenal axis at peripheral level. Ghrelin administration directly into the paraventricular nucleus of the hypothalamus also induces c-fos within the CRF-producing neurons and the hypothalamic-pituitary-adrenal axis, without any significant effect on the food intake. Interestingly, dual-label immunohistochemical analysis and ghrelin binding studies failed to show GHSR expression in CRF neurons. Thus, we conclude that ghrelin activates hypophysiotropic CRF neurons, albeit indirectly.

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    • "channels affects neurotransmitter release in hypothalamic GABAergic neurons. This is particularly relevant, as it has been reported that -amino butyric acid (GABA) release is essential for regulating food intake (Wu et al., 2009), and that GHSR1a activity decreases inhibitory input of hypothalamic networks (Cabral et al., 2012). To make such studies density by GPCRs was reported previously for Ca v 2.2 channels complexed with nociceptin (ORL1) and dopamine (D1 and D2) receptors (Zamponi, 2015). "

    The Journal of General Physiology 09/2015; 146(3). DOI:10.1085/jgp.201511462 · 4.79 Impact Factor
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    • "Ghrelin is also produced in small amounts by other organs like heart, lung, lymphatic tissue, kidney, adrenal glands, thyroid gland, pancreas, gonads, some neoplastic tissues and cancer-cell lines [16] [17] [18]. Ghrelin-immunoreactive neurons are present in few regions of the brain like the arcuate and the ventromedial nucleus of the hypothalamus, cerebellum and brainstem [13] [19] [20] [21]. Ghrelin is also present in placenta along GH, GHRH, somatostatin and insulin-like growth factor 1 (IGF1) which shows that it is also involved in fetal growth [22]. "
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    ABSTRACT: Abstract Background: Ghrelin is a type of growth hormone (GH) secretagogue that stimulates the release of growth hormone (GH). It is a first hormone linking gastrointestinal-pituitary axis. Objective: This review highlights the interaction of ghrelin with GHRH and somatostatin to regulate the secretion of GH and intends to explore the possible physiological role of the ghrelin-pituitary-GH axis linkage system. Observation: Ghrelin is highly conserved among species and is classified into octanoylated (C8:0), decanoylated (C10:0), decenoylated (C10:1) and nonacylated,ghrelin. Acylated ghrelin is the major active form of human ghrelin. The primary production site of ghrelin is the stomach, and it interacts with stomach ghrelin as well as hypothalamic GHRH and somatostatin in the regulation of pituitary GH secretion. Ghrelin stimulate GH release through the GHS receptor to increase intracellular Ca2+ ([Ca2+] levels via IP3 signal transduction pathway. Ghrelin is a specific endogenous ligand for the GHS receptor and provides a definitive proof of the occurance of a GHS–GHS receptor signalling system in the regulation of GH secretion. Conclusion: Studies suggests that ghrelin is a powerful pharmacological agent that exerts a potent, time-dependent stimulation of pulsatile secretion of GH. Keywords : Ghrelin, Growth Hormone, Ghrelin-Pituitary-Gh Axis Linkage System
    Journal of Clinical and Diagnostic Research 08/2014; 8(8):MC13-MC-17. DOI:10.7860/JCDR/2014/9863.4767 · 0.23 Impact Factor
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    • "Ghrelin was reported to activate hypophysiotropic CRH neurons in rodents, resulting in activation of the hypothalamic-pituitary-adrenal (HPA) axis through CRH [35] [36] [37], and to increases plasma CORT concentrations [36]. "
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    ABSTRACT: Ghrelin, the endogenous ligand for growth hormone secretagogue receptor 1a (GHS-R1a), stimulates food intake in mammals centrally and peripherally. In contrast, central injection of ghrelin inhibits feeding in neonatal chicks (Gallus gallus), which is thought to be mediated by the corticotrophin-releasing hormone (CRH) system, indicating that the mechanisms underlying ghrelin’s action are different in chicks and mammals. However, the interaction between the ghrelin system and the CRH system has not been fully clarified in chicks. In the present study, we examined the effect of intracerebroventricular (ICV) injection of CRH and urocortin-3 (UCN-3), a CRH family peptide and an endogenous ligand for the CRH type-2 receptor (CRH-R2), on synthesis and secretion of ghrelin in chicks. ICV injection of UCN-3 but not CRH increased plasma ghrelin concentration (P < 0.05), diencephalic mRNA expression of ghrelin and GHS-R1a (P < 0.05), and tended to decrease ghrelin (P = 0.08) and GHS-R1a (P = 0.10) mRNA expression in the proventriculus. Moreover, ICV injection of UCN-3 tended to increase diencephalic mRNA expression of CRH-R2 (P = 0.08) while CRH had no effect on it. In addition, ICV injection of CRH but not UCN-3 increased plasma corticosterone concentration (P < 0.05) and decreased the diencephalic mRNA expression of CRH-R1 (P < 0.05). These results clearly indicate that the roles of the CRH system for the ghrelin system are divided. The present study suggests that UCN-3 is mainly involved in the ghrelin system in chicks perhaps through the CRH-R2.
    Domestic animal endocrinology 04/2014; 47(1). DOI:10.1016/j.domaniend.2013.12.002 · 2.17 Impact Factor
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