Neuroendocrine and peripheral activities of ghrelin: implications in metabolism and obesity

Muccioli, Giampiero; Tschöp, Matthias H.; Papotti, Mauro; Deghenghi, Romano; Heiman, Mark L.; Ghigo, Ezio

doi:10.1016/s0014-2999(02)01432-2

Cited by 347 publications

(382 citation statements)

References 154 publications

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“…In addition, the GHRP-6-and GHRH-induced release of GH was lower in the old versus the young dogs, although this difference was not statistically significant. These observations are compatible with findings in humans, showing that not only the GH-releasing effect of ghrelin (Broglio et al, 2003) but also that of GHRH and peptidyl or non-peptidyl synthetic GHSs undergoes an age-related decrease (Aloi et al, 1994;Bowers et al, 1992;Broglio et al, 2003;Chapman et al, 1996;Muccioli et al, 2002). In old rats, the GH response to synthetic GHSs is impaired as well (Ceda et al, 1986;Walker et al, 1990).…”

Section: Discussionsupporting

confidence: 85%

“…Additionally, the age-related decrease of the GH response to ghrelin and synthetic GHSs agrees with the well-known in vitro hyporesponsiveness of the aged somatotroph cells to the majority of provocative stimuli, including Ghrelin GHRH NaCl GHRP-6 Ghrelin GHRH NaCl GHRP-6 Ghrelin GHRH NaCl GHRP-6 Ghrelin GHRH NaCl GHRP-6 Ghrelin GHRH NaCl GHRP-6 Ghrelin GHRH NaCl GH (µg/L) . GHRH, despite the availability of a remarkable GHreleasable pool (Giustina and Veldhuis, 1998;Ghigo et al, 1999;Muccioli et al, 2002). These observations support the idea that the somatopause is driven primarily by the hypothalamus and that the pituitary somatotropes retain their capacity to synthesise and secrete adequate levels of GH (Cella et al, 1993;Corpas et al, 1992;Franchimont et al, 1989;Muccioli et al, 2002;Muller et al, 1999;Walker et al, 1990).…”

Section: Discussionmentioning

confidence: 84%

“…Also in old dogs, the GH responsiveness to the synthetic GHS hexarelin has been reported to be low (Cella et al, 1995). The GH-releasing activity of ghrelin and synthetic GHSs depends on the functional integrity of the hypothalamus-pituitary unit (Muccioli et al, 2002). In humans, it has been demonstrated that the age-related reduction of both spontaneous and stimulated GH secretion reflects age-related changes in the neural control of somatotrope function (Giustina and Veldhuis, 1998;Ghigo et al, 1999).…”

Section: Discussionmentioning

confidence: 99%

“…A decline of GHS-Rs in the ageing brain (Arvat et al, 1998;Muccioli et al, 2002) could further explain the reduced GH response to ghrelin/GHSs in elderly humans. Based on the relative great age-related decline in the GH response to ghrelin compared with that to GHRH in dogs, it may be hypothesised that also in dogs GHS-R expression decreases considerably with age.…”

Section: Discussionmentioning

confidence: 99%

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Effects of growth hormone secretagogues on the release of adenohypophyseal hormones in young and old healthy dogs

Bhatti

Duchateau

Ham

et al. 2006

The Veterinary Journal

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The effects of three growth hormone secretagogues (GHSs), ghrelin, growth hormone-releasing peptide-6 (GHRP-6), and growth hormone-releasing hormone (GHRH), on the release of adenohypophyseal hormones, growth hormone (GH), adrenocorticotropic hormone (ACTH), thyroid-stimulating hormone (TSH), luteinising hormone (LH), prolactin (PRL) and on cortisol were investigated in young and old healthy Beagle dogs.Ghrelin proved to be the most potent GHS in young dogs, whereas in old dogs GHRH administration was associated with the highest plasma GH concentrations. The mean plasma GH response after administration of ghrelin was significantly lower in the old dogs compared with the young dogs. The mean plasma GH concentration after GHRH and GHRP-6 administration was lower in the old dogs compared with the young dogs, but this difference did not reach statistical significance. In both age groups, the GHSs were specific for GH release as they did not cause significant elevations in the plasma concentrations of ACTH, cortisol, TSH, LH, and PRL. It is concluded that in young dogs, ghrelin is a more powerful stimulator of GH release than either GHRH or GHRP-6. Ageing is associated with a decrease in GH-releasing capacity of ghrelin, whereas this decline is considerably lower for GHRH or GHRP-6.

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Section: Discussionsupporting

confidence: 85%

Section: Discussionmentioning

confidence: 84%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

See 2 more Smart Citations

Effects of growth hormone secretagogues on the release of adenohypophyseal hormones in young and old healthy dogs

Bhatti

Duchateau

Ham

et al. 2006

The Veterinary Journal

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“…GHS were discovered as a family of non-natural peptidyl and non-peptidyl molecules able to strongly stimulate GH secretion acting on a specific Gprotein coupled receptor, namely GHS type 1a receptor, that is different from the GHRH-receptor (Smith et al, 1997;Muccioli et al, 1998Muccioli et al, , 2002. Theoretically, GHS would therefore influence cardiac structure and function via enhanced GH and IGF-I secretion.…”

Section: Introductionmentioning

confidence: 99%

Cardiac effects of ghrelin and its endogenous derivatives des-octanoyl ghrelin and des-Gln14-ghrelin

Bedendi

Alloatti

Marcantoni

et al. 2003

European Journal of Pharmacology

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169

116

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The mechanisms underlying the cardiac activities of synthetic growth hormone secretagogues (GHS) are still unclear. The natural ligand of the GHS receptors, i.e. ghrelin, classically binds the GHS receptor and exerts endocrine actions in acylated forms only; its cardiovascular actions still need to be investigated further. In order to clarify these aspects, we studied the effects of either the synthetic peptidyl GHS hexarelin (1 AM), or the natural ghrelin (50 nM) and the endogenous ghrelin derivatives des-Gln 14 -ghrelin (1 -100 nM) and des-octanoyl ghrelin (50 nM), on the tension developed by guinea pig papillary muscle and on L-type Ca 2 + current (I Ca ) of isolated ventricular cells. The binding of these molecules to ventricular cell membrane homogenates was also studied. We observed that all peptides reduced the tension developed at low frequencies (60 -120 beats/min) in a dose-dependent manner. No alteration in cardiac contractility was induced by desGln 14 -ghrelin or des-octanoylated ghrelin when the endocardial endothelium had been removed or after cyclooxygenase blockade. Pretreatment with tyramine (2 AM) had no effect on the inotropic response induced by des-Gln 14 -ghrelin. No significant effect on I Ca of isolated ventricular cells was observed in the presence of des-Gln 14 -ghrelin (100 nM). The order of potency on the tension of papillary muscle was: des-octanoyl ghrelin>ghrelin = des-Gln 14 -ghrelin>hexarelin. This gradient of potency was consistent with the binding experiments performed on ventricular membranes where either acylated or unacylated ghrelin forms, and hexarelin, recognized a common high-affinity binding site. In conclusion, ghrelin, des-Gln 14 -ghrelin and des-octanoyl ghrelin, show similar negative inotropic effect on papillary muscle; as des-octanoyl ghrelin is peculiarly devoid of any GH-releasing activity, the cardiotropic action of these molecules is independent of GH release. The binding studies and the experiments performed both on the isolated cells and on papillary muscle after endothelium removal or cyclooxygenase blockade indicate that the cardiotropic action of natural and synthetic ghrelin analogues reflects the interaction with a novel GHS receptor (peculiarly common for ghrelin and des-octanoyl ghrelin), leading to release of cyclooxygenase metabolites from endothelial cells, as indicated by direct measurement of prostacyclin metabolite 6-keto-PGF 1a .

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Semisynthesis of human ghrelin: Condensation of a Boc‐protected recombinant peptide with a synthetic O‐acylated fragment

et al. 2005

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The creation of peptide using a combination of recombinant expression and chemical synthesis can be a powerful tool for the production of a wide variety of polypeptides modified by phosphorylation, glycosylation, etc. We have developed a new method for the preparation of a recombinant peptide with a free N(alpha)-amino group and protected N(epsilon)-amino groups, and have used this method in the semisynthesis of human ghrelin. Ghrelin, a natural ligand for growth hormone secretagogue receptor, is a 28-residue peptide with an essential n-octanoyl modification on Ser3. A 7-residue N-terminal fragment of ghrelin containing the octanoyl modification was prepared by Fmoc chemistry. In the preparation of it, all reactions were performed on the 2-chlorotrityl resin. Additionally, TBDMS and tBu turned out to be the most effective protection groups for the Ser3 and the Ser2, Ser6, respectively. For preparation of a 21-residue C-terminal fragment, we established a two-step protease processing method for the partially protected segment. A recombinant precursor peptide was Boc protected and subsequently cleaved using two distinct proteases, OmpT and Kex2. The peptides were then coupled to each other and, after deprotection, resulted in fully active human ghrelin.

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Neuroendocrine and peripheral activities of ghrelin: implications in metabolism and obesity

Cited by 347 publications

References 154 publications

Effects of growth hormone secretagogues on the release of adenohypophyseal hormones in young and old healthy dogs

Effects of growth hormone secretagogues on the release of adenohypophyseal hormones in young and old healthy dogs

Cardiac effects of ghrelin and its endogenous derivatives des-octanoyl ghrelin and des-Gln14-ghrelin

Semisynthesis of human ghrelin: Condensation of a Boc‐protected recombinant peptide with a synthetic O‐acylated fragment

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