Ghrelin... very interesting peptide

Ghrelin was discovered as the peptide hormone that potently stimulates release of growth hormone from the anterior pituitary. It was subsequently determined that ghrelin, along with several other hormones, has significant effects on appetite and energy balance. The predominant source of ghrelin is epithelial cells in the stomach.

Please read this study, very promising so far. It mentions of studies being done on humans. If this intrests you and u have free time, help me dig up some more info on it.

http://arbl.cvmbs.colostate.edu/hbooks/pathphys/endocrine/gi/ghrelin.html

Interrelationship between the Novel Peptide Ghrelin and Somatostatin/Growth Hormone-Releasing Hormone in Regulation of Pulsatile Growth Hormone Secretion
Gloria S. Tannenbaum, Jacques Epelbaum and Cyril Y. Bowers
Departments of Pediatrics and of Neurology and Neurosurgery (G.S.T.), McGill University, and the Neuropeptide Physiology Laboratory, McGill University-Montréal Children’s Hospital Research Institute, Montreal, Québec, Canada H3H 1P3; Institut National de la Santé et de la Recherche Médicale, Unité 549 (J.E.), 75014 Paris, France; and Department of Medicine, Division of Endocrinology, Tulane University Medical Center (C.Y.B.), New Orleans, Louisiana 70112-2699

Address all correspondence and requests for reprints to: Dr. Gloria S. Tannenbaum, Neuropeptide Physiology Laboratory, McGill University-Montréal Children’s Hospital Research Institute, 2300 Tupper Street, Montréal, Québec, Canada H3H 1P3. E-mail: [email protected].

GH is an anabolic hormone that is essential for normal linear growth and has important metabolic effects throughout life. The ultradian rhythm of GH secretion is generated by the intricate patterned release of two hypothalamic hormones, somatostatin (SRIF) and GHRH, acting both at the level of the pituitary gland and within the central nervous system. The recent discovery of ghrelin, a novel GH-releasing peptide identified as the endogenous ligand for the GH secretagogue receptor and shown to induce a positive energy balance, suggests the existence of an additional neuroendocrine pathway for GH control. To further understand how ghrelin interacts with the classical GHRH/SRIF neuronal system in GH regulation, we used a combined physiological and histochemical approach. Our physiological studies of the effects of ghrelin on spontaneous pulsatile GH secretion in conscious, free-moving male rats demonstrate that 1) ghrelin, administered either systemically or centrally, exerts potent, time-dependent GH-releasing activity under physiological conditions; 2) ghrelin is a functional antagonist of SRIF, but its GH-releasing activity at the pituitary level is not dependent on inhibiting endogenous SRIF release; 3) SRIF antagonizes the action of ghrelin at the level of the pituitary gland; and 4) the GH response to ghrelin in vivo requires an intact endogenous GHRH system. Our dual chromogenic and autoradiographic in situ hybridization experiments provide anatomical evidence that ghrelin may directly modulate GHRH mRNA- and neuropeptide Y mRNA-containing neurons in the hypothalamic arcuate nucleus, but that SRIF mRNA-expressing cells are not major direct targets for ghrelin. Together, these findings support the idea that ghrelin may be a critical hormonal signal of nutritional status to the GH neuroendocrine axis serving to integrate energy balance and the growth process.

If i am interpreting this study correctly, it says that ghrelin causes diferentiation(they either mature or become more effective at storing fat) of fat cells. That is definately not what we want. Maybe this isnt a good idea after all!


The Role of Ghrelin and Growth Hormone Secretagogues Receptor on Rat Adipogenesis
Kichoon Choi, Sang-Gun Roh, Yeon-Hee Hong, Yogendra B. Shrestha, Daisuke Hishikawa, Chen Chen, Masayasu Kojima, Kenji Kangawa and Shin-Ichi Sasaki
Department of Food Resource Science (K.C., S.-G.R., Y.-H.H., Y.B.S., D.H., S.S.), Faculty of Agriculture, Shinshu University, Nagano-ken 399-4598, Japan; Endocrine Cell Biology (C.C.), Prince Henry’s Institute of Medical Research, Clayton 3168, Australia; Molecular Genetics (M.K.), Institute of Life Science, Kurume University, Aikawamachi 2432-3, Kurume, Fukuoka 839-0861, Japan; and Department of Biochemistry (K.K.), National Cardiovascular Center Research Institute, Fujishirodai, Suita, Osaka 565-8565, Japan

Address all correspondence and requests for reprints to: Dr. Sang-gun Roh, Department of Food Resource Science Faculty of Agriculture, Shinshu University Nagano-ken 399-4598, Japan. E-mail: [email protected].

Recent research progress indicates a close link between ghrelin, a natural ligand of GH secretagogues receptor (GHS-R), and both the metabolic balance and body composition. To clarify the involvement of ghrelin and GHS-R in the process of adipogenesis, we measured the expression of GHS-R and peroxisome proliferator-activated receptor 2 (PPAR-2) mRNA in rat adipocytes using semiquantitative RT-PCR methods. The levels of GHS-R mRNA increased by up to 4-fold in adipose tissue from epididymal and parametrial regions as the rat aged from 4–20 wk and were significantly elevated during the differentiation of preadipocytes in vitro. Ghrelin (10-8 M for 10 d) stimulated the activity of glycerol-3-phosphate dehydrogenase and the differentiation of rat preadipocytes in vitro. Ghrelin treatment also significantly increased the levels of PPAR-2 mRNA in primary cultured rat differentiated adipocytes. In addition, isoproterenol (10-8 M, 40 min)-stimulated lipolysis was significantly reduced by simultaneous ghrelin treatment in a dose-dependent manner in vitro. In conclusion, the expression of GHS-R in rat adipocytes increases with the age and during adipogenesis. Ghrelin in vitro stimulates the differentiation of preadipocytes and antagonizes lipolysis. Ghrelin may therefore play an important role in the process of adipogenesis in rats.

interesting info

bump it up for more information, very interesting, maybe instnt knows about this stuff more

Ghrelin (A Brain-gut Peptide Stimulates Growth Hormone Secretion and Food Intake)

1. Matthias TschoÈ p, David L. Smiley & Mark L. Heiman.
Ghrelin induces adiposity in rodents. Nature, 407, 908-913 (2000)

The discovery of the peptide hormone ghrelin, an endogenous ligand for the growth hormone secretagogue (GHS) receptor, yielded the surprising result that the principal site of ghrelin synthesis is the stomach and not the hypothalamus.

Although ghrelin is likely to regulate pituitary growth hormone (GH) secretion along with GH-releasing hormone and somatostatin, GHS receptors have also been identified on hypothalamic neurons and in the brainstem.

Apart from potential paracrine effects, ghrelin may thus offer an endocrine link between stomach, hypothalamus and pituitary, suggesting an involvement in regulation of energy balance. Here we show that peripheral daily administration of ghrelin caused weight gain by reducing fat utilization in mice and rats. Intracerebroventricular administration of ghrelin generated a dose-dependent increase in food intake and body weight. Rat serum ghrelin concentrations were increased by fasting and were reduced by re-feeding or oral glucose administration, but not by water ingestion. We propose that ghrelin, in addition to its role in regulating GH secretion, signals the hypothalamus when an increase in metabolic efficiency is necessary.


2. A. M. Wren, C. J. Small, H. L. Ward, K. G. Murphy, C. L. Dakin, S. Taheri, A. R. Kennedy, G. H. Roberts, D. G. A. Morgan, M. A. Ghatei, and S. R. Bloom.
The Novel Hypothalamic Peptide Ghrelin Stimulates Food Intake and Growth Hormone Secretion. Endocrinology 141: 4325-4328, 2000

Ghrelin, a novel 28 amino acid peptide found in hypothalamus and stomach, was recently identified as the endogenous ligand for the growth hormone secretagogue receptor (GHS-R). We have now found that both intracerebroventricular (ICV) and intraperitoneal (i.p.) administration of ghrelin in freely feeding rats stimulated food intake. The onset of increased feeding was rapid and after ICV administration was sustained for 24 hours. Following ICV administration of 3nmol ghrelin, the duration and magnitude of the feeding stimulation was similar to that following 5nmol neuropeptide Y (NPY). Plasma growth hormone (GH) concentration increased following both ICV and i.p. administration of ghrelin. Release of adrenocorticotrophic hormone (ACTH) was stimulated and thyroid stimulating hormone (TSH) inhibited following ICV administration of ghrelin. These data suggest a possible role for the newly identified endogenous hypothalamic peptide, ghrelin, in stimulation of feeding and growth hormone secretion. (Endocrinology 141: 4325-4328, 2000)



3.Yukari Date, Masayasu Kojima, Hiroshi Hosoda, Akira Sawaguchi, Muhtashan S. Mondal, Tatsuo Suganuma, Shigeru Matsukura, Kenji Kangawa, and Masamitsu Nakazato.
Ghrelin, a Novel Growth Hormone-Releasing Acylated Peptide, Is Synthesized in a Distinct Endocrine Cell Type in the Gastrointestinal Tracts of Rats and Humans. Endocrinology 141: 4255-4261, 2000

Ghrelin, a novel GH-releasing acylated peptide, was recently isolated from rat stomach. It stimulated the release of GH from the anterior pituitary through the GH secretagogue receptor (GHS-R). Ghrelin messenger RNA and the peptide are present in rat stomach, but its cellular source has yet to be determined. Using two different antibodies against the N- and C-terminal regions of rat ghrelin, we identified ghrelin-producing cells in the gastrointestinal tracts of rats and humans by light and electron microscopic immunohistochemistry and in situ hybridization combined with immunohistochemistry. Ghrelin-immunoreactive cells, which are not enterochromaffin-like cells, D cells, or enterochromaffin cells, accounted for about 20% of the endocrine cell population in rat and human oxyntic glands. Rat ghrelin was present in round, compact, electron-dense granules compatible with those of X/A-like cells whose hormonal product and physiological functions have not previously been clarified. The localization, population, and ultrastructural features of ghrelin-producing cells (Gr cells) indicate that they are X/A-like cells. Ghrelin also was found in enteric endocrine cells of rats and humans. Using two RIAs for the N- and C-terminal regions of ghrelin, we determined its content in the rat gastrointestinal tract. Rat ghrelin was present from the stomach to the colon, with the highest content being in the gastric fundus. Messenger RNAs of ghrelin and GHS-R also were found in these organs. Ghrelin probably functions not only in the control of GH secretion, but also in the regulation of diverse processes of the digestive system. Our findings provide clues to additional, as yet undefined, physiological functions of this novel gastrointestinal hormone.


4. Date Y, Murakami N, Kojima M, Kuroiwa T, Matsukura S, Kangawa K, Nakazato M.
Central effects of a novel acylated peptide, ghrelin, on growth hormone release in rats. Biochem Biophys Res Commun 2000 Aug 28;275(2):477-80

Ghrelin, a novel growth-hormone-releasing acylated peptide, was recently isolated from rat stomach by the search of an endogenous ligand to an "orphan" G-protein-coupled-receptor. Ghrelin neuron is present in the arcuate nucleus of rat hypothalamus, but its central effect on growth hormone (GH) release has yet to be clarified. We determined the plasma GH concentration and GH mRNA level in the pituitary in response to central administration of ghrelin. A single intracerebroventricular (ICV) administration of ghrelin to rats increased the plasma GH concentration dose-dependently. A continuous ICV administration of ghrelin via osmotic pump for 12 days increased the plasma GH concentration on day 6, but did not keep the high GH concentration on day 12. The GH mRNA levels in both groups of single and continuous administration of ghrelin were not significantly different from those of controls. A single administration of growth-hormone secretagogue also did not stimulate GH synthesis. Central ghrelin stimulated GH release but did not augment GH synthesis. In addition to gastric ghrelin, hypothalamic ghrelin functions to regulate GH release.



5. Masuda Y, Tanaka T, Inomata N, Ohnuma N, Tanaka S, Itoh Z, Hosoda H, Kojima M, Kangawa K.
Ghrelin stimulates gastric acid secretion and motility in rats.

Biochem Biophys Res Commun 2000 Oct 5;276(3):905-8
Ghrelin, a novel growth-hormone-releasing peptide, was discovered in rat and human stomach tissues. However, its physiological and pharmacological actions in the gastric function remain to be determined. Therefore, we studied the effects of rat ghrelin on gastric functions in urethane-anesthetized rats. Intravenous administrations of rat ghrelin at 0.8 to 20 &mgr;g/kg dose-dependently increased not only gastric acid secretion measured by a lumen-perfused method, but also gastric motility measured by a miniature balloon method. The maximum response in gastric acid secretion was almost equipotent to that of histamine (3 mg/kg, i.v.). Moreover, these actions were abolished by pretreatment with either atropine (1 mg/kg, s.c.) or bilateral cervical vagotomy, but not by a histamine H(2)-receptor antagonist (famotidine, 1 mg/kg, s.c.). These results taken together suggest that ghrelin may play a physiological role in the vagal control of gastric function in rats.


6. Arvat E, Di Vito L, Broglio F, Papotti M, Muccioli G, Dieguez C, Casanueva FF, Deghenghi R, Camanni F, Ghigo E.
Preliminary evidence that Ghrelin, the natural GH secretagogue (GHS)-receptor ligand, strongly stimulates GH secretion in humans. J Endocrinol Invest 2000 Sep;23(8):493-5

An endogenous ligand for the GH secretagogue-receptor (GHS-R) has been recently purified from rat and human stomach and named Ghrelin. It has been demonstrated that Ghrelin specifically stimulates GH secretion from rat pituitary cells in culture as well as in rats in vivo. In this preliminary study, in 4 normal adults [age (mean+/-SE): 28.6+/-3.5 yr; body mass index (BMI): 22.3+/-2.1 kg/m2] we administered 1.0 microg/kg Ghrelin or GHRH-29 to compare their GH-releasing activities in humans. In all subjects Ghrelin induced a prompt, marked and long-lasting increase in circulating GH levels (peak: 107.9+/-26.1 microg/l; AUC: 6503.1+/-1632.7 microg/l/h). The GH response to Ghrelin was clearly higher (p<0.05) than that after GHRH (peak: 22.3+/-4.5 microg/l; AUC: 1517.5+/-338.4 microg/l/h). In conclusion, this preliminary study shows that Ghrelin exerts a strong stimulatory effect on GH secretion in humans releasing more GH than GHRH.

Scientists Report Active Ghrelin Fragments and Ghrelin Antagonist
Ghrelin: Endogenous Growth-Hormone Releasing Peptide with Novel Regulatory Mechanism

Human growth hormone (hGH) is secreted throughout life. hGH is implicated as an important factor in the aging process due to its significant decrease over the life cycle, and its involvement in many processes, such as fat, protein, carbohydrate, muscle, and bone metabolism. Therefore, hGH has been hailed by the popular press as the fountain of youth.



Small synthetic molecules called growth-hormone secretagogues (GHSs) stimulate the release of growth hormone (GH) from the pituitary through human secretagogue receptor 1a (hGHSR1a) (1, 2, 3). The endogenous ligand for this receptor was identified in 1999 as ghrelin (4). Kojima and co-workers reported ghrelin to be an octanoylated, 28-residue peptide with the n-octanoyl group at Ser3, the first observed to date. Ghrelin stimulates GH-release from rat primary cultured pituitary cells in a dose-dependent manner (EC50 = 2.1 nM) and it induces an increase of intracellular Ca2+ in GHS-R-expressing cells with EC50 of 2.5 nM (4). Rat and human peptide sequences are identical except for the amino acid substitutions at positions 11 and 12.

Although ghrelin and the known hypothalamic peptide, growth-hormone releasing factor, stimulate GH-release, they differ both in GH secretion mechanism and in a structural aspect, the octanoyl group attached on the side chain of Ser3 in ghrelin is essential for expressing activity. This octanoylated posttranslational modification is the first of this type observed to date. The major ghrelin-producing tissue is the stomach and ghrelin immunoreactivity is found in healthy human blood. Recently Merck scientists, Bednarek and coworkers, report that only the first 5 residues are necessary to maintain the activity of endogenous ghrelin, but a large hydrophobic group on the Ser3 side chain is still required for activity (3).

This peptide may constitute a new regulatory mechanism for GH-release. It is conceivable that ghrelin may have other functions in some tissues other than pituitary, because the GHS receptor is expressed in heart, lung, pancreas, intestine, and adipose tissue.

1. R.G. Smith, K. Cheng, W.R. Schoen, S.-S. Pong, G. Hickey, T. Jacks, B. Butler, W. W.-S. Chan, L.-Y. P. Chaung, F. Judith, J. Taylor, M. J. Wyvratt, and M.H. Fisher, Science, 260, 1640 (1993).
2. C.Y. Bowers, Cell. Mol. Life Sci., 54, 1316 (1998).
3. M.A. Bednarek, S.D. Feighner, S.-S. Pong, K.K. McKee, D.L. Hreniuk, M.V. Silva, V.A. Warren, A.D. Howard, L.H.Y. Van der Ploeg, and J.V. Heck, J. Med. Chem., 43, 4370-4376 (2000).
4. M. Kojima, H. Hosoda, Y. Date, M. Nakazato, H. Matsuo, and K. Kangawa, Nature, 402, 656 (1999). (Original)


New! Ghrelin Antagonist and Non-Acylated Ghrelin Now Available

Recently, Holst and coworkers reported a substance P analog to be a low potency ghrelin antagonist. In 1988, [D-Arg1,D-Phe5,D-Trp7,9,Leu11]-Substance P was originally reported by Woll et al. to be a potent bombesin antagonist able to inhibit small cell lung cancer growth in vitro. Now the Danish researchers have found this ghrelin antagonist to be a full inverse agonist with an EC50 = 5.2 nM.

Also, Broglio and coworkers recently reported des-octanoyl ghrelin peptide did not possess endocrine activity in animal models. However, Des-n-Octanoyl-[Ser3]-Ghrelin (Human) was shown to be as effective as ghrelin in exhibiting antiproliferative effects on tumor cell lines in in vitro studies.

These new products, non-acylated ghrelin and ghrelin antagonist, should serve as a valuable research tool to aid diabetes and obesity research efforts. In addition, ghrelin active and inactive (negative control) fragments, are available from Peptides International.

http://www.pepnet.com/ghrelin.html

any ideas on what this means: Central ghrelin stimulated GH release but did not augment GH synthesis. In addition to gastric ghrelin, hypothalamic ghrelin functions to regulate GH release.

From the readings i found, the research was leading to the fact that although there was substantial gh release, there seemed to result in weight gain from fat! this is the exact opposite of how gh works so they are not really sure what is going on there. this is a clip from biggerstronger's first post on it, towards the beginning of study:
Here we show that peripheral daily administration of ghrelin caused weight gain by reducing fat utilization in mice and rats.

this has been leading to greater fat accumulation in the rats. for now i dont think there is enough known about the substance to date.

There have been studies that link high ghrelin levels to obesity. This could explain part of your question. I don't fully understand how this substance works. Bump for more info.

wow as always good read, big byrd and bigger stronger