Peripheral injection of ghrelin induces Fos expression in the dorsomedial hypothalamic nucleus in rats

Kobelt, Peter; Wisser, Anna-Sophia; Stengel, Andreas; Goebel, Miriam; Inhoff, Tobias; Noetzel, Steffen; Veh, Rüdiger W.; Bannert, Norbert; Voort, I. van der; Wiedenmann, Bertram; Klapp, Burghard F.; Taché, Yvette; Mönnikes, Hubert

doi:10.1016/j.brainres.2008.01.054

Cited by 49 publications

(35 citation statements)

References 46 publications

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“…It has been reported that peripheral administration of ghrelin can induce c-fos expression, a marker of neuronal activation, in the brain (38). In this study, we have also observed an increase of c-fos expression in the brainstem of aged septic rats after combined treatment.…”

Section: Combined Human Ghrelin and Gh Activates Brain Activity In Agsupporting

confidence: 81%

Combined Administration of Human Ghrelin and Human Growth Hormone Attenuates Organ Injury and Improves Survival in Aged Septic Rats

Yang

Zhou

et al. 2016

Mol Med

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Sepsis is a major healthcare concern, especially in the elderly population. The use of an animal model closely resembling clinical conditions in this population may provide a better prediction in translating bench studies to the bedside. Ghrelin inhibits sympathetic nerve activity and inflammation in young septic animals; however, aged animals become hyporesponsive to ghrelin. In this study, we evaluated the efficacy of combined human ghrelin and growth hormone (GH) for sepsis treatment in the elderly utilizing a clinically relevant animal model of sepsis. Male Fischer 344 rats 22 to 24 months old were subjected to cecal ligation and puncture (CLP). Human ghrelin plus GH or vehicle (normal saline) was administered subcutaneously at 5 h after CLP. At 20 h after CLP, blood and tissue samples were collected for various analyses. Combined treatment attenuated serum levels of lactate, lactate dehydrogenase, creatinine, blood urea nitrogen, interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) in aged septic rats. The integrity of the microscopic structure in the lungs, liver and kidneys was well preserved after treatment. Expression of IL-6, TNF-α, macrophage inflammatory protein-2 and keratinocyte-derived chemokine as well as myeloperoxidase activity and caspase-3 activation were significantly reduced in the lungs and liver of treated rats. Moreover, treated rats showed an improvement in cardiovascular function and increased expression of ghrelin receptor and c-fos in the brainstem. Finally, the 10-d survival of aged septic rats was increased from 29% to 64% after combined treatment and was associated with less body weight loss. Our findings warrant the development of combined human ghrelin and GH for sepsis treatment in the geriatric population.

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Section: Combined Human Ghrelin and Gh Activates Brain Activity In Agsupporting

confidence: 81%

Combined Administration of Human Ghrelin and Human Growth Hormone Attenuates Organ Injury and Improves Survival in Aged Septic Rats

Yang

Zhou

et al. 2016

Mol Med

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“…However, Kobelt et al . (2008) did not find any change in c-Fos positive neurons in the NTS after peripheral administration of AG [17]. Unacylated ghrelin (UAG) also occurs in the circulation [13].…”

Section: Introductionmentioning

confidence: 94%

Unacylated Ghrelin Suppresses Ghrelin-Induced Neuronal Activity in the Hypothalamus and Brainstem of Male Rats

et al. 2014

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Ghrelin, the endogenous growth hormone secretagogue, has an important role in metabolic homeostasis. It exists in two major molecular forms: acylated (AG) and unacylated (UAG). Many studies suggest different roles for these two forms of ghrelin in energy balance regulation. In the present study, we compared the effects of acute intracerebroventricular administration of AG, UAG and their combination (AG+UAG) to young adult Wistar rats on food intake and central melanocortin system modulation. Although UAG did not affect food intake it significantly increased the number of c-Fos positive neurons in the arcuate (ARC), paraventricular (PVN) and solitary tract (NTS) nuclei. In contrast, UAG suppressed AG-induced neuronal activity in PVN and NTS. Central UAG also modulated hypothalamic expression of Mc4r and Bmp8b, which were increased and Mc3r, Pomc, Agrp and Ucp2, which were decreased. Finally, UAG, AG and combination treatments caused activation of c-Fos in POMC expressing neurons in the arcuate, substantiating a physiologic effect of these peptides on the central melanocortin system. Together, these results demonstrate that UAG can act directly to increase neuronal activity in the hypothalamus and is able to counteract AG-induced neuronal activity in the PVN and NTS. UAG also modulates expression of members of the melanocortin signaling system in the hypothalamus. In the absence of an effect on energy intake, these findings indicate that UAG could affect energy homeostasis by modulation of the central melanocortin system.

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“…While the c-Fos immunolabeling technique can provide information regarding increases in neuronal activity, decreases in activity brought about by membrane hyperpolarization cannot be identified. Indeed, some c-Fos immunolabeling studies have reported that ghrelin does not induce c-Fos in the AP (34) or induces only weak immunolabeling (56) and suggested that AP is not an important site of action within the CNS. The fact that 19% of the neurons modulated by ghrelin in this study were hyperpolarized suggests that previous studies have underestimated the ability of AP to detect circulating ghrelin and communicate this information to other sites involved in regulation of energy homeostasis.…”

Section: Discussionmentioning

confidence: 99%

“…Injection of ghrelin into the NTS or nearby areas stimulated feeding at doses below the threshold required for forebrain injections (17). Many investigators observe that peripheral administration of ghrelin also caused increases in caudal brain stem c-Fos immunoreactivity (24,37,38,56), although such changes have not been reported in all studies (34). Moreover, recent observations by Gilg and Lutz (21) have convincingly demonstrated a role for AP in ghrelin-mediated feeding.…”

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confidence: 99%

Ghrelin modulates electrical activity of area postrema neurons

Fry¹,

Ferguson²

2009

American Journal of Physiology-Regulatory, Integrative and Comp

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Ghrelin, a peptide hormone secreted from the stomach, is known to have a potent appetite-stimulating activity. Recently, it has been shown that area postrema (AP), a caudal brain stem center that lacks a blood-brain barrier, is a key site of activity for ghrelin in stimulating appetite and regulating pancreatic protein secretion. In this study, we have examined the ability of ghrelin to regulate the electrical activity of area postrema neurons using patch-clamp electrophysiology. Using current-clamp configuration, we found that at a concentration of 10 nM, ghrelin caused inhibition in 19% of neurons tested, while a further 19% were excited by similar application of ghrelin. The remaining 62% of AP neurons were insensitive to ghrelin. These effects were concentration dependent, with an apparent EC 50 of 1.9 nM. Voltage-clamp recordings revealed that ghrelin caused a potentiation of voltage-gated K ϩ currents in neurons that exhibited a hyperpolarization and a potentiation of a depolarizing nonspecific cation current (NSCC) in those neurons that exhibited a depolarization of membrane potential. These are the first data showing that ghrelin exerts a direct effect on electrical activity of AP neurons and supports the notion that ghrelin can act via the AP to regulate energy homeostasis. patch clamp; action potential; sensory circumventricular organ; energy homeostasis GHRELIN IS AN ACYLATED 28-amino acid peptide hormone, which was discovered on the basis of its activity as an endogenous ligand for the growth hormone secretagogue receptor (GHSR) (35). Originally isolated from the stomach, ghrelin has also been shown to be expressed in various tissues, including the duodenum, adrenal gland, lung, and gonads (22), as well as in neurons in the hypothalamus (11). In addition to its role in the stimulation of growth hormone release in the pituitary, ghrelin is thought to play several roles in the regulation of energy balance. Circulating levels of ghrelin are increased in the fasting state and in anticipation of food (2, 12, 13). Conversely, ghrelin levels are attenuated by feeding and the presence of nutrients in the stomach (58), or by treatment with leptin (2). Administration of ghrelin potently stimulates food intake in rats (58, 64, 65), mice (2), and humans (63). These studies suggest a physiological role in initiation of feeding. Ghrelin is also suggested to play a role in long-term regulation of energy balance, as chronic administration of ghrelin causes weight gain by reducing fat utilization as an energy source (58). Lastly, ghrelin also plays a role in the digestion of food and the stimulation of gastric motility, acid secretion, and pancreatic protein secretion (38, 41).There is considerable interest as to the mechanism by which ghrelin exerts its appetite-stimulating effects, and, in particular, the site of action of ghrelin in the central nervous system (CNS). For example, the neuropeptide Y/Agouti-related peptide (NPY/AGRP) neurons within the arcuate nucleus of the hypothalamus (ARC) are suggested by many t...

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Peripheral injection of ghrelin induces Fos expression in the dorsomedial hypothalamic nucleus in rats

Cited by 49 publications

References 46 publications

Combined Administration of Human Ghrelin and Human Growth Hormone Attenuates Organ Injury and Improves Survival in Aged Septic Rats

Combined Administration of Human Ghrelin and Human Growth Hormone Attenuates Organ Injury and Improves Survival in Aged Septic Rats

Unacylated Ghrelin Suppresses Ghrelin-Induced Neuronal Activity in the Hypothalamus and Brainstem of Male Rats

Ghrelin modulates electrical activity of area postrema neurons

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