Neural basis of orexigenic effects of ghrelin acting within lateral hypothalamus

Olszewski, Pawel K.; Li, Dehong; Grace, Martha K.; Billington, Charles J.; Kotz, Catherine M.; Levine, Allen S.

doi:10.1016/s0196-9781(03)00105-0

Cited by 137 publications

(91 citation statements)

References 31 publications

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“…Ghrelin-containing axons project to the LH and form direct synaptic contact with orexin-producing neurons (57). Intracerebroventricular or local application of ghrelin into the LH of rats activates orexin cells (24,37,57,67). Orexinergic mechanisms may contribute to the feeding effects of ghrelin since pretreatment with orexin antibodies attenuates ghrelin-induced eating and the effect of ghrelin was significantly reduced in orexin-deficient mice (57).…”

Section: Discussionmentioning

confidence: 99%

Ghrelin microinjection into forebrain sites induces wakefulness and feeding in rats

Szentirmai¹,

Kapás²,

Krueger³

2007

American Journal of Physiology-Regulatory, Integrative and Comp

110

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Szentirmai É , Kapás L, Krueger JM. Ghrelin microinjection into forebrain sites induces wakefulness and feeding in rats. Am J Physiol Regul Integr Comp Physiol 292: R575-R585, 2007. First published August 17, 2006; doi:10.1152/ajpregu.00448.2006.-Ghrelin, a gutbrain peptide, is best known for its role in the stimulation of feeding and growth hormone release. In the brain, orexin, neuropeptide Y (NPY), and ghrelin are parts of a food intake regulatory circuit. Orexin and NPY are also implicated in maintaining wakefulness. Previous experiments in our laboratory revealed that intracerebroventricular injections of ghrelin induce wakefulness in rats. To further elucidate the possible role of ghrelin in the regulation of arousal, we studied the effects of microinjections of ghrelin into hypothalamic sites, which are implicated in the regulation of feeding and sleep, such as the lateral hypothalamus (LH), medial preoptic area (MPA), and paraventricular nucleus (PVN) on sleep in rats. Sleep responses, motor activity, and food intake after central administration of 0.04, 0.2, or 1 g (12, 60, or 300 pmol) ghrelin were recorded. Microinjections of ghrelin into the LH had strong wakefulness-promoting effects lasting for 2 h. Wakefulness was also stimulated by ghrelin injection into the MPA and PVN; the effects were confined to the first hour after the injection. Ghrelin's non-rapid-eye-movement sleepsuppressive effect was accompanied by attenuation in the electroencephalographic (EEG) slow-wave activity and changes in the EEG power spectrum. Food consumption was significantly stimulated after microinjections of ghrelin into each hypothalamic site. Together, these results are consistent with the hypothesis that forebrain ghrelinergic mechanisms play a role in the regulation of vigilance, possibly through activating the components of the food intake-and arousalpromoting network formed by orexin and NPY. lateral hypothalamus; medial preoptic area; paraventricular nucleus; electroencephalogram; slow-wave activity; sleep GHRELIN IS A 28-AMINO ACID peptide produced by endocrine cells in the gastrointestinal system and by neurons in the central nervous system (21). Circulating ghrelin is derived mainly from the stomach (1). Plasma ghrelin levels inversely correlate with feeding; fasting increases, while food intake reduces, plasma ghrelin concentrations (7, 61). In the brain, ghrelin is produced by arcuate nucleus (ARC) neurons and by a distinct hypothalamic neuronal population in the internuclear region (6). Ghrelin's actions are mediated by the growth hormone secretagogue receptor (GHS-R) (21). GHS-R mRNA is widely distributed in the gastrointestinal tract, sensory vagus fibers, and the brain. Those hypothalamic nuclei that are implicated in the regulation of feeding and/or sleep-wake activity, such as the lateral hypothalamus (LH), paraventricular nucleus (PVN), ARC, dorsomedial hypothalamic nucleus, anteroventral preoptic nucleus, anterior hypothalamic area, suprachiasmatic nucleus, anterolateral hypothalamic nucleus, and the...

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Section: Discussionmentioning

confidence: 99%

Ghrelin microinjection into forebrain sites induces wakefulness and feeding in rats

Szentirmai¹,

Kapás²,

Krueger³

2007

American Journal of Physiology-Regulatory, Integrative and Comp

110

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“…Studies in rodents exploring the precise parenchymal targets for ghrelin's orexigenic effects have identified a number of candidate sites: orexigenic responses have been observed when injected into discrete brain areas that include the hypothalamus (arcuate nucleus, ventromedial nucleus, dorsomedial nucleus, paraventricular nucleus, lateral hypothalamus) (Olszewski et al 2003a;Olszewski et al 2003b;, the nucleus tractus solitarius of the brainstem (Faulconbridge et al 2003), the central nucleus of the amygdala (Olszewski et al 2003) and mesolimbic reward areas (the ventral tegmental area (VTA) and nucleus accumbens (N.Acc) Naleid et al 2005). Activation of hypothalamic and brainstem areas could be of importance for ghrelin's effects on homeostatic feeding that is driven by metabolic need.…”

Section: The Central Ghrelin Signalling Systemmentioning

confidence: 99%

The role of the central ghrelin system in reward from food and chemical drugs

Dickson

Egecioglu

Landgren

et al. 2011

Molecular and Cellular Endocrinology

217

168

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Here we review recent advances that identify a role for the central ghrelin signalling system in reward from both natural rewards (such as food) and artificial rewards (that include alcohol and drugs of abuse). Whereas ghrelin emerged as a stomach-derived hormone involved in energy balance, hunger and meal initiation via hypothalamic circuits, it now seems clear that it also has a role in motivated reward-driven behaviours via activation of the so-called "cholinergic-dopaminergic reward link". This reward link comprises a dopamine projection from the ventral tegmental area (VTA) to the nucleus accumbens together with a cholinergic input, arising primarily from the laterodorsal tegmental area. Ghrelin administration into the VTA or LDTg activates the "cholinergicdopaminergic" reward link, suggesting that ghrelin may increase the incentive value of motivated behaviours such as reward-seeking behaviour ("wanting" or "incentive motivation"). Further, direct injection of ghrelin into the brain ventricles or into the VTA

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“…GHS-R expression was demonstrated in neurons within the hypothalamus and injections of ghrelin into discrete hypothalamic nuclei or the forebrain ventricles increased food intake (Lawrence et al, 2002;Nakazato et al, 2001;Shintani et al, 2001). The arcuate nucleus of the hypothalamus (Arc) is strongly implicated in the mediation of the hyperphagic response to ghrelin (Cowley et al, 2003;Currie et al, 2005;Hewson and Dickson, 2000;Olszewski et al, 2003a;Olszewski et al, 2003b;Ruter et al, 2003;Wren et al, 2000). Tamura et al, (2002), for example, showed that ablation of Arc neurons by neonatal MSG treatment eliminated the feeding response to lateral intracerebroventricular (i.c.v.)…”

Section: Introductionmentioning

confidence: 99%

Caudal brainstem delivery of ghrelin induces fos expression in the nucleus of the solitary tract, but not in the arcuate or paraventricular nuclei of the hypothalamus

et al. 2008

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Ghrelin increases food intake when injected into either the forebrain or hindbrain ventricles. Brain areas activated by ghrelin after forebrain delivery have been examined using Fos immunohistochemistry and include the hypothalamic arcuate (Arc) and paraventricular (PVN) nuclei, and the nucleus of the solitary tract (NTS) in the medulla. It is not clear, however, if ghrelin applied directly to the hindbrain activates forebrain structures. Therefore, we examined Fos expression in the Arc, PVN, and NTS after injecting ghrelin into the fourth ventricle. Animals treated with a hyperphagic dose of ghrelin had greater levels of Fos expression in the NTS at the level of the area postrema than animals injected with vehicle. Ghrelin did not, however, increase Fos expression in the Arc or PVN in rats with open or occluded cerebral aqueducts. Given the importance of caudal brainstem (CBS) catecholamine pathways in the control of food intake, we performed double-labeling experiments to evaluate the potential overlap between tyrosine hydroxylase TH and ghrelin-induced Fos expression. Ghrelin did not increase Fos in TH-positive neurons in the NTS, suggesting that ghrelin delivered to the fourth ventricle does not act through catecholaminergic pathways. Nevertheless, the local (NTS), but not distal (Arc and PVN), induction of Fos suggests the presence of partially independent forebrain and hindbrain circuits that respond to ghrelin. These data support the NTS as a target of ghrelin action by building upon prior findings of increases in food intake in response to third-and fourth-ventricle ghrelin delivery. SectionRegulatory Systems

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Neural basis of orexigenic effects of ghrelin acting within lateral hypothalamus

Cited by 137 publications

References 31 publications

Ghrelin microinjection into forebrain sites induces wakefulness and feeding in rats

Ghrelin microinjection into forebrain sites induces wakefulness and feeding in rats

The role of the central ghrelin system in reward from food and chemical drugs

Caudal brainstem delivery of ghrelin induces fos expression in the nucleus of the solitary tract, but not in the arcuate or paraventricular nuclei of the hypothalamus

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