Regulation of Growth Hormone Secretagogue Receptor Gene Expression in the Arcuate Nuclei of the Rat by Leptin and Ghrelin

Nogueiras, Rubén; Tovar, Sulay; Mitchell, Sharon E.; Rayner, D V; Archer, Zoe A.; Diéguez, Carlos; Williams, Lynda M.

doi:10.2337/diabetes.53.10.2552

Cited by 126 publications

(115 citation statements)

References 58 publications

(38 reference statements)

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“…Although the number of POMC ghrelin-labeled neurons remained unchanged, as would be expected from a neuronal population that displays minimal activity in the fasted state (41), we observed a reversible increase in the number of NPY ghrelin-labeled neurons following 24-h fasting. These results appear to be consistent with the physiological necessity to secure robust feeding responses following a fasting period, the direct correlation between quantity of ingested food and number of stimulated NPY neurons (39), the increase in GHS-R mRNA expression in the ARH following short-term fasting (42,43), and the regulation by nutritional state of the effects of ghrelin on Fos protein expression in the ARH (17,44). The unique vmARH milieu irrigated by fenestrated capillaries may therefore not only provide a niche for neurogenic tanycytes (45) but may also support a population of "scout neurons" that are able to rapidly sense peripheral signals and coordinate more global responses.…”

Section: Discussionsupporting

confidence: 67%

Rapid sensing of circulating ghrelin by hypothalamic appetite-modifying neurons

Schaeffer

Langlet

Lafont

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

246

188

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To maintain homeostasis, hypothalamic neurons in the arcuate nucleus must dynamically sense and integrate a multitude of peripheral signals. Blood-borne molecules must therefore be able to circumvent the tightly sealed vasculature of the blood-brain barrier to rapidly access their target neurons. However, how information encoded by circulating appetite-modifying hormones is conveyed to central hypothalamic neurons remains largely unexplored. Using in vivo multiphoton microscopy together with fluorescently labeled ligands, we demonstrate that circulating ghrelin, a versatile regulator of energy expenditure and feeding behavior, rapidly binds neurons in the vicinity of fenestrated capillaries, and that the number of labeled cell bodies varies with feeding status. Thus, by virtue of its vascular connections, the hypothalamus is able to directly sense peripheral signals, modifying energy status accordingly.hormone diffusion | in vivo imaging | median eminence | metabolism C ontinuous integration of peripheral signals by neurons belonging to the arcuate nucleus of the hypothalamus (ARH) is critical for central regulation of energy balance and neuroendocrine function (1). To dynamically report alterations to homeostasis and ensure an appropriate neuronal response, blood-borne factors such as hormones must rapidly access the central nervous system (CNS). This is particularly evident in the case of food intake, which is regulated by a plethora of circulating satiety signals (2) whose levels fluctuate in an ultradian manner. Despite this, it remains unclear how key energy status-signaling hormones such as ghrelin can be rapidly sensed by target neurons to alter feeding responses (3). Elucidation of the mechanisms underlying molecule entry into the brain is important for understanding not only normal maintenance of homeostasis but also how this is perturbed during common pathologies such as obesity and diabetes (4, 5).Although molecule transport mechanisms within the ARH are poorly characterized, they likely assume one of two forms. First, chronic feedback may be accomplished by uptake of circulating molecules into the ARH via saturable receptor-mediated transport at the level of the choroid plexus and/or bloodbrain barrier (BBB) (6-9). Second, the ARH is morphologically located in close apposition to the median eminence (ME), a circumventricular organ composed of fenestrated capillaries. Because these vessels project toward the ventromedial ARH (vmARH), they could represent a direct vascular input for passive diffusion of peripheral molecules into the hypothalamus (10-13). So far, study of the functional importance of fenestrated capillaries in molecule entry into the metabolic brain has been impeded by lack of appropriate tools.To evaluate the role of fenestrated ME/ARH capillaries in rapid detection of peripheral signals by the hypothalamus, we used a recently developed in vivo imaging approach to visualize in real time the extravasation of fluorescent molecules (14). Ghrelin was chosen as a candidate hormone because i...

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Section: Discussionsupporting

confidence: 67%

Rapid sensing of circulating ghrelin by hypothalamic appetite-modifying neurons

Schaeffer

Langlet

Lafont

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

246

188

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“…In rats, a nearly 300% increase in GHS-R mRNA expression relative to controls was observed 2 h after intracerebroventricular injection of 5 μg ghrelin (Nogueiras et al, 2004). Channel catfish GHS-R1a mRNA expression increased 364% in the pituitary 2 h after IP injection of ghrelin-Gly (Small et al, 2009).…”

Section: Discussionmentioning

confidence: 92%

Sequence, genomic organization and expression of ghrelin receptor in grass carp, Ctenopharyngodon idellus

Cai

Yuan

et al. 2015

Comparative Biochemistry and Physiology Part A: Molecular &

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“…Indeed, feeding status affects not only ghrelin secretion but also the expression of its receptor in the CNS (Nogueiras et al, 2004;Sun et al, 2004;Tups et al, 2004). In particular, ghrelin receptor levels were increased eightfold in the rat hypothalamus after 48 h of fasting (Kim et al, 2003), indicating that there is a finely tuned regulation of ghrelin and its receptor contributing to energy balance mechanisms.…”

Section: Discussionmentioning

confidence: 99%

Ghrelin Effects on the Circadian System of Mice

Yannielli

Molyneux²,

Harrington³

et al. 2007

J. Neurosci.

118

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The orexigenic peptide ghrelin stimulates both food intake and growth hormone release and is synthesized in the stomach and in hypothalamic areas involved in feeding control. The suprachiasmatic nuclei of the hypothalamus (SCN) control most circadian rhythms, although there is evidence that some oscillators, such as food-entrainable oscillators, can drive activity rhythms even after SCN ablation. Ghrelin levels exhibit a circadian rhythm and closely follow feeding schedules, making this peptide a putative candidate for food-related entraining signals. We examined the response of the SCN to ghrelin treatments in vitro, by means of electrophysiological and bioluminescence recordings, and in vivo, by assessing effects on the phase of locomotor activity rhythms. Ghrelin applied at circadian time 6 in vitro to cultured SCN slices induced an ϳ3 h phase advance. In addition, ghrelin phase advanced the rhythm of PER2::LUC (Period2::Luciferase) expression in cultured SCN explants from mPer2Luc transgenic mice. In vivo, intraperitoneal administration of ghrelin or a synthetic analog, growth hormone-releasing protein-6 (GHRP-6), to ad libitum fed animals failed to alter circadian phase. When injected after 30 h of food deprivation, GHRP-6 induced a phase advance compared with saline-injected animals. These results indicate that ghrelin may play a role in the circadian system by exerting a direct action on the SCN and that the system as a whole may become sensitive to ghrelin and other feeding-related neuropeptides under conditions of food restriction.

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Regulation of Growth Hormone Secretagogue Receptor Gene Expression in the Arcuate Nuclei of the Rat by Leptin and Ghrelin

Cited by 126 publications

References 58 publications

Rapid sensing of circulating ghrelin by hypothalamic appetite-modifying neurons

Rapid sensing of circulating ghrelin by hypothalamic appetite-modifying neurons

Sequence, genomic organization and expression of ghrelin receptor in grass carp, Ctenopharyngodon idellus

Ghrelin Effects on the Circadian System of Mice

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