Fabio Broglio
University of Turin
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Featured researches published by Fabio Broglio.
Journal of Cell Biology | 2002
Gianluca Baldanzi; Nicoletta Filigheddu; Santina Cutrupi; Filomena Catapano; Sara Bonissoni; Alberto Fubini; Daniela Malan; Germano Baj; Riccarda Granata; Fabio Broglio; Mauro Papotti; Nicola Surico; Federico Bussolino; Jörgen Isgaard; Romano Deghenghi; Fabiola Sinigaglia; Maria Prat; Giampiero Muccioli; Ezio Ghigo; Andrea Graziani
Ghrelin is an acyl-peptide gastric hormone acting on the pituitary and hypothalamus to stimulate growth hormone (GH) release, adiposity, and appetite. Ghrelin endocrine activities are entirely dependent on its acylation and are mediated by GH secretagogue (GHS) receptor (GHSR)-1a, a G protein–coupled receptor mostly expressed in the pituitary and hypothalamus, previously identified as the receptor for a group of synthetic molecules featuring GH secretagogue (GHS) activity. Des-acyl ghrelin, which is far more abundant than ghrelin, does not bind GHSR-1a, is devoid of any endocrine activity, and its function is currently unknown. Ghrelin, which is expressed in heart, albeit at a much lower level than in the stomach, also exerts a cardio protective effect through an unknown mechanism, independent of GH release. Here we show that both ghrelin and des-acyl ghrelin inhibit apoptosis of primary adult and H9c2 cardiomyocytes and endothelial cells in vitro through activation of extracellular signal–regulated kinase-1/2 and Akt serine kinases. In addition, ghrelin and des-acyl ghrelin recognize common high affinity binding sites on H9c2 cardiomyocytes, which do not express GHSR-1a. Finally, both MK-0677 and hexarelin, a nonpeptidyl and a peptidyl synthetic GHS, respectively, recognize the common ghrelin and des-acyl ghrelin binding sites, inhibit cell death, and activate MAPK and Akt. These findings provide the first evidence that, independent of its acylation, ghrelin gene product may act as a survival factor directly on the cardiovascular system through binding to a novel, yet to be identified receptor, which is distinct from GHSR-1a.
Journal of Endocrinological Investigation | 2000
Emanuela Arvat; L. Di Vito; Fabio Broglio; Mauro Papotti; Giampiero Muccioli; Carlos Dieguez; Felipe F. Casanueva; Romano Deghenghi; F. Camanni; Ezio Ghigo
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 μg/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 μg/l; AUC: 6503.1±1632.7 μg/l/h). The GH response to Ghrelin was clearly higher (p<0.05) than that after GHRH (peak: 22.3±4.5 μg/l; AUC: 1517.5±338.4 μg/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.
Clinical Endocrinology | 2005
Ezio Ghigo; Fabio Broglio; Emanuela Arvat; Mauro Maccario; Mauro Papotti; Giampiero Muccioli
Ghrelin, an acylated peptide produced predominantly by the stomach, has been discovered to be a natural ligand of the growth hormone secretagogue receptor type 1a (GHS‐R1a). Ghrelin has recently attracted considerable interest as a new orexigenic factor. However, ghrelin exerts several other neuroendocrine, metabolic and also nonendocrine actions that are explained by the widespread distribution of ghrelin and GHS‐R expression. The likely existence of GHS‐R subtypes and evidence that the neuroendocrine actions, but not all the other actions, of ghrelin depend on its acylation in serine‐3 revealed a system whose complexity had not been completely explored by studying synthetic GHS. Ghrelin secretion is mainly regulated by metabolic signals and, in turn, the modulatory action of ghrelin on the control of food intake and energy metabolism seems to be among its most important biological actions. However, according to a recent study, ghrelin‐null mice are neither anorectics nor dwarfs and this evidence clearly depicts a remarkable difference from leptin null mice. Nevertheless, the original and fascinating story of ghrelin, as well as its potential pathophysiological implications in endocrinology and internal medicine, is not definitively cancelled by these data as GHS‐R1a null aged mice show significant alterations in body composition and growth, in glucose metabolism, cardiac function and contextual memory. Besides potential clinical implications for natural or synthetic ghrelin analogues acting as agonists or antagonists, there are several open questions awaiting an answer. How many ghrelin receptor subtypes exist? Is ghrelin ‘the’ or just ‘a’ GHS‐R ligand? That is, are there other natural GHS‐R ligands? Is there a functional balance between acylated and unacylated ghrelin forms, potentially with different actions? Within the next few years suitable answers to these questions will probably be found, making it possible to gain a better knowledge of ghrelins potential clinical perspectives.
Endocrine | 2001
Ezio Ghigo; Emanuela Arvat; Roberta Giordano; Fabio Broglio; Laura Gianotti; Mauro Maccario; Gianni Bisi; Andrea Graziani; Mauro Papotti; Giampiero Muccioli; Romano Deghenghi; F. Camanni
Growth hormone secretagogues (GHSs) are synthetic peptidyl and nonpeptidyl molecules with strong, dose-dependent, and reproducible growth hormone (GH)-releasing activity even after oral administration. GHSs release GH via actions on specific receptors (GHS-R) at the pituitary and, mainly, at the hypothalamic levels. GHSs likely act as functional somatostatin antagonists and meantime enhance the activity of GH-releasing hormone (GHRH)-secreting neurons. The GH-releasing effect of GHSs is independent of gender but undergoes marked age-related variations. Estrogens play a major role in enhancing the GH response to GHSs at puberty, which GHRH hypoactivity, somatostatinergic hyperactivity and impaired activity of the putative GHS-like ligand and receptors probably explain the reduced GH-releasing effect of GHSs in aging. The activity of GHSs is not fully specific for GH. Their slight prolactin-releasing activity probably comes from direct pituitary action. In physiological conditions, the ACTH-releasing activity of GHSs is dependent on central actions; a direct action on GHS-R in pituitary ACTH-secreting tumors likely explains the peculiar ACTH and cortisol hyperresponsiveness to GHSs in Cushing disease. GHSs have specific receptor subtypes in other central and peripheral endocrine and nonendocrine tissues mediating GH-independent biologic activities. GHSs influence sleep pattern, stimulated food intake, and have cardiovascular activities. GHs have specific binding in normal and neoplastic follicular derived human thyroid tissue and inhibit the proliferation of follicular-derived neoplastic cell lines. The discovery of ghrelin, a 28 amino acid peptide synthesized in the stomach but also in other tissues, has opened new fascinating perspectives of research in this field.
Journal of Endocrinological Investigation | 2003
Fabio Broglio; Andrea Benso; Cristina Gottero; Flavia Prodam; C. Gauna; L. Filtri; Emanuela Arvat; A. J. van der Lely; Romano Deghenghi; Ezio Ghigo
Ghrelin, a 28-amino acid peptide predominantly produced by the stomach, displays strong GH-releasing activity mediated by the GH secretagogue (GHS)-receptor (GHS-R) type 1a at the hypothalamus-pituitary level. Ghrelin and synthetic GHS also possess other GH-independent peripheral endocrine and non-endocrine activities via the activation of peripheral GHS-R subtypes. In rats in vivo non-acylated ghrelin has been reported devoid of any endocrine activity; however, in vitro, it has been shown as effective as ghrelin in exerting anti-proliferative activity on tumor cell lines. The aim of the present study was to clarify whether non-acylated human ghrelin shares some of the endocrine activities of its acylated form in humans. To this goal, the effects of acylated or non-acylated ghrelin (1.0 μg/kg iv at 0 min) on GH, PRL, ACTH, F, insulin and glucose levels were studied in two different testing sessions in 7 normal young volunteers (age [mean±SE]: 24.3±1.7 yr; BMI: 21.5±0.9 kg/m2). The effects of placebo administration were also studied. The administration of acylated ghrelin induced prompt and marked increase in circulating GH levels (AUC: 5452.4±904.9 μg*min/l; p<0.01 vs placebo) and significant increase in PRL (1273.5±199.7 μg*min/l; p<0.01 vs placebo), ACTH (4482.7±954.4 pg*min/ml; p<0.01 vs placebo) and F levels (15985.0±1141.9 μg*min/l; p<0.01 vs placebo). Its administration was also followed by decrease in insulin levels (1448.67±137.9 mU*min/l; p<0.05 vs placebo) that was coupled with an increase in plasma glucose levels (10974.2±852.5 mg*min/dl; p<0.05 vs placebo). The administration of non-acylated ghrelin and that of placebo did not induce any change in the hormonal parameters or in glucose levels. In conclusion, this study shows that in humans nonacylated ghrelin does not possess the pituitaric and pancreatic endocrine activities of human ghrelin octanoylated in Serine 3.
Journal of Endocrinological Investigation | 2002
Simonetta Bellone; A. Rapa; Daniela Vivenza; N. Castellino; Antonella Petri; J. Bellone; E. Me; Fabio Broglio; Flavia Prodam; Ezio Ghigo; Gianni Bona
Ghrelin, a natural GH secretagogue, exerts remarkable endocrine and non-endocrine activities such as orexigenic effect and modulation of the endocrine and metabolic response to variations in energy balance. Ghrelin levels have been reported to be negatively associated to insulin secretion, enhanced in anorexia and reduced in obesity. Ghrelin levels in childhood have never been evaluated. We measured morning ghrelin levels after overnight fasting in 29 healthy lean children (NC) and in 36 obese children (OBC). The results were compared with those recorded twice in 3 different sessions in healthy lean adults (NA). In NA ghrelin levels showed good within-subject reproducibility without gender-related differences. Ghrelin levels in NC [(median; 25°–75° centile): 426.0; 183.0–618.0 pg/ml] were similar to those in NA (380.5; 257.7–551.7 pg/ml). Ghrelin levels in OBC (229.5; 162.5–339.5 pg/ml) were lower (p<0.03) than in NC (426.0; 183.0–618.0 pg/ml). Both in NC and in OBC, ghrelin levels were independent of gender and pubertal status. In all children, ghrelin levels were negatively associated (p<0.05) to weight excess (r=−0.24), insulin (r=−0.28) and IGF-I (r=−0.4) levels. In conclusion, these findings demonstrate that morning ghrelin levels after overnight fasting show good within-subject reproducibility, and are similar in both sexes and do not vary from childhood to adulthood. In childhood, circulating ghrelin levels are reduced in obese subjects being negatively correlated to overweight and insulin secretion.
Hormone Research in Paediatrics | 2003
Fabio Broglio; Cristina Gottero; Emanuela Arvat; Ezio Ghigo
Ghrelin is a 28-amino-acid peptide predominantly produced by the stomach. Substantially lower amounts were detected in bowel, pancreas, kidneys, the immune system, placenta, testes, pituitary, and hypothalamus. Ghrelin displays strong growth hormone (GH)-releasing action mediated by the activation of the so-called GH secretagogue (GHS) receptor (GHS-R) type 1a. GHS-R are concentrated in the hypothalamus-pituitary unit but are also distributed in other central and peripheral tissues. Apart from the potent GH-releasing action, ghrelin has other actions including stimulation of lactotroph and corticotroph function, influence on the pituitary gonadal axis, stimulation of appetite, control of energy balance, influence on sleep and behavior, control of gastric motility and acid secretion, influence on exocrine and endocrine pancreatic function as well as on glucose metabolism, cardiovascular actions and modulation of proliferation of neoplastic cells, as well as of the immune system. The discovery of ghrelin opened many new perspectives of research in neuroendocrinology and metabolism, and even also in other fields of internal medicine as gastroenterology, immunology, oncology and cardiology. The possibility that ghrelin and/or GHS analogs, acting as either agonists or antagonists on different activities, might have clinical impact is obviously suggested and is receiving great attention.
The Journal of Clinical Endocrinology and Metabolism | 2008
Fabio Lanfranco; Lorenza Bonelli; Matteo Baldi; Elisa Me; Fabio Broglio; Ezio Ghigo
CONTEXT Recent evidence suggests that ghrelin exerts a negative modulation on the gonadal axis. Ghrelin was reported to suppress LH secretion in both animal and human models. Moreover, acylated ghrelin (AG) also decreases the LH responsiveness to GnRH in vitro. OBJECTIVE The objective of the study was to evaluate the effects of AG infusion on spontaneous and stimulated gonadotropin secretion. DESIGN, PARTICIPANTS, AND INTERVENTION In seven young healthy male volunteers (age mean +/- sem 26.4 +/- 2.6 yr), we evaluated LH and FSH levels every 15 min during: 1) iv isotonic saline infusion; 2) iv saline followed by AG; LH and FSH response to GnRH (100 microg iv as a bolus), 3) alone and 4) during AG infusion; LH and FSH response to naloxone (0.1 mg/kg iv as a slow bolus), 5) alone and 6) during AG infusion. RESULTS Significant LH but not FSH pulses were recorded in all subjects under saline infusion. AG infusion inhibited LH levels [area under the curve((240-480)): 415.8 +/- 69.7 mIU/ml.min during AG vs. 744.6 +/- 120.0 mIU/ml.min during saline, P < 0.02] and abolished LH pulsatility. No change in FSH secretion was recorded. The LH and FSH responses to GnRH during saline were not affected by AG administration. However, AG inhibited the LH response to naloxone [area under the curve ((120-210)): 229.9 +/- 39.3 mIU/ml.min during AG vs. 401.1 +/- 44.6 mIU/ml.min during saline, P < 0.01]. FSH levels were not modified by naloxone alone or in combination with AG. CONCLUSIONS AG inhibits both spontaneous LH pulsatility and the LH response to naloxone. Because AG does not affect the LH response to GnRH, these findings indicate that the ghrelin system mediates central inhibition of the gonadal axis.
Clinical Endocrinology | 2002
Lidia Di Vito; Fabio Broglio; Andrea Benso; Cristina Gottero; Flavia Prodam; Mauro Papotti; Giampiero Muccioli; Carlos Dieguez; Felipe F. Casanueva; Romano Deghenghi; Ezio Ghigo; Emanuela Arvat
objective Ghrelin, a 28‐amino‐acid peptide purified from the stomach and showing a unique structure with an n‐octanoyl ester at the serine 3 residue, is a natural ligand of the GH secretagogue (GHS) receptor (GHS‐R). Ghrelin strongly stimulates GH secretion in both animals and humans, showing a synergistic effect with GH‐releasing hormone (GHRH) but no interaction with synthetic GHS. However, the activity of ghrelin as well as that of non‐natural GHS is not fully specific for GH; ghrelin also induces a stimulatory effect on lactotroph and corticotroph secretion, at least in humans.
Nature Clinical Practice Endocrinology & Metabolism | 2007
Petra Wiedmer; Ruben Nogueiras; Fabio Broglio; David A. D'Alessio; Matthias H. Tschöp
The high prevalence of obesity and diabetes will lead to higher rates of morbidity and mortality. The search for drugs to treat these metabolic disorders has, therefore, intensified. The stomach-derived peptide ghrelin regulates food intake and body weight. Recent work suggests that ghrelin also controls glucose metabolism. In addition, current evidence suggests that most of the actions of ghrelin could contribute to the metabolic syndrome. The ghrelin signaling system is, therefore, a promising target for the development of new drugs for the treatment of obesity and diabetes. Agents that block the ghrelin signaling system might be especially useful targets. This Review summarizes the potential and the limitations of ghrelin as a tool to better understand, prevent and treat obesity and diabetes.