hexarelin and Body-Weight

Hexarelin is a recently synthesized small growth hormone releasing peptide (GHRP) (His-D-2-methyl-Trp-Ala-Trp-D-Phe-Lys- NH2). It is active by intravenous, oral and intranasal administration in animals and man. The aim of this study was to find out whether long-term administration of this peptide would promote growth in short children.. Intranasal hexarelin was administered in a dose of 60 micrograms/kg thrice daily to 8 prepubertal short children aged 4-11.6 years for periods of up to 8 months.. Hexarelin treatment stimulated insulin-like growth factor-I (IGF-I) secretion raising the level from 10.4 +/- 3.9 (SD) to 14.1 +/- 4.6 nmol/l (P < 0.004). The rise in IGF-I led to a significant increase in the mean (+/- SD) linear growth velocity from 5.3 +/- 0.8 to 8.3 +/- 1.7 cm/year (P < 0.0001). There was also a significant decrease in skinfold thickness despite increase in body weight and an increase in head circumference. Additional findings were a rise in serum phosphate from 1.5 +/- 0.1 to 1.8 +/- 0.1 mmol/l (P < 0.004) and of alkaline phosphatase from 219 +/- 74 to 261 +/- 75 U/l (P < 0.05).. The long-term GH/IGF-I stimulating, anabolic and growth promoting effects achieved by intranasal administration of this hexapeptide, seemingly without undesirable side-effects, suggests clinical potential for this new class of drugs.

Topics: Administration, Intranasal; Alkaline Phosphatase; Body Weight; Cephalometry; Child; Child, Preschool; Drug Administration Schedule; Female; Growth Disorders; Growth Substances; Hormones; Humans; Insulin-Like Growth Factor I; Male; Oligopeptides; Phosphates; Skinfold Thickness; Stimulation, Chemical

Chemotherapy can cause cachexia, which consists of weight loss associated with muscle atrophy. The exact mechanisms underlying this skeletal muscle toxicity are largely unknown and co-therapies to attenuate chemotherapy-induced side effects are lacking. By using a rat model of cisplatin-induced cachexia, we here characterized the mitochondrial homeostasis in tibialis anterior cachectic muscle and evaluated the potential beneficial effects of the growth hormone secretagogues (GHS) hexarelin and JMV2894 in this setting. We found that cisplatin treatment caused a decrease in mitochondrial biogenesis (PGC-1α, NRF-1, TFAM, mtDNA, ND1), mitochondrial mass (Porin and Citrate synthase activity) and fusion index (MFN2, Drp1), together with changes in the expression of autophagy-related genes (AKT/FoxO pathway, Atg1, Beclin1, LC3AII, p62) and enhanced ROS production (PRX III, MnSOD). Importantly, JMV2894 and hexarelin are capable to antagonize this chemotherapy-induced mitochondrial dysfunction. Thus, our findings reveal a key-role played by mitochondria in the mechanism responsible for GHS beneficial effects in skeletal muscle, strongly indicating that targeting mitochondrial dysfunction might be a promising area of research in developing therapeutic strategies to prevent or limit muscle wasting in cachexia.

Topics: Animals; Autophagy; Biomarkers; Body Weight; Cachexia; Cisplatin; Disease Models, Animal; Forkhead Box Protein O3; Growth Hormone; Indoles; Male; Mitochondria; Mitochondrial Dynamics; Muscle, Skeletal; Oligopeptides; Organ Size; Organelle Biogenesis; Oxidative Stress; Phosphorylation; Piperidines; Proto-Oncogene Proteins c-akt; Rats; Secretagogues; Triazoles

The ability of the gut hormone ghrelin to promote positive energy balance is mediated by the growth hormone secretagogue receptor (GHSR). GHSR is a G protein-coupled receptor (GPCR) that is found centrally and peripherally and that can signal in a ligand-independent manner basally or when heterodimerized with other GPCRs. However, current Ghsr knockout models cannot dissect ghrelin-dependent and ghrelin-independent signaling, precluding assessment of the physiological importance of these signaling pathways. An animal model carrying a Ghsr mutation that preserves GHSR cell surface abundance, but selectively alters GHSR signaling, would be a useful tool to decipher GHSR signaling in vivo. We used rats with the Ghsr(Q343X) mutation (Ghsr(M/M)), which is predicted to delete the distal part of the GHSR carboxyl-terminal tail, a domain critical for the signal termination processes of receptor internalization and β-arrestin recruitment. In cells, the GHSR-Q343X mutant showed enhanced ligand-induced G protein-dependent signaling and blunted activity of processes involved in GPCR signal termination. Ghsr(M/M)rats displayed enhanced responses to submaximal doses of ghrelin or GHSR agonist. Moreover, Ghsr(M/M)rats had a more stable body weight under caloric restriction, a condition that increases endogenous ghrelin tone, whereas under standard housing conditions,Ghsr(M/M)rats showed increased body weight and adiposity and reduced glucose tolerance. Overall, our data stress the physiological role of the distal domain of GHSR carboxyl terminus as a suppressor of ghrelin sensitivity, and we propose using the Ghsr(M/M)rat as a physiological model of gain of function in Ghsr to identify treatments for obesity-related conditions.

Topics: Adiposity; Administration, Intravenous; Animals; Appetite; beta-Arrestin 1; Blood Glucose; Body Weight; Caloric Restriction; Eating; Female; Ghrelin; Glucose Tolerance Test; Growth Hormone; HEK293 Cells; Humans; Male; Microscopy, Confocal; Mutation; Oligopeptides; Rats; Receptors, Ghrelin; Signal Transduction

Ghrelin, a 28-amino-acid peptide isolated from the stomach, is the natural ligand of the GH-secretagogues receptor-1a (GHS-R1a) and, so far, the only discovered circulating appetite-stimulating hormone. Similarly to ghrelin, many synthetic compounds belonging to the GHS family stimulate both GH secretion and feeding, whereas some stimulate GH secretion only. In the past years, studies have focused on the potential of the GHS to stimulate GH release during long-term treatment in humans and experimental animals. Few data are available about the extraendocrine effects of the GHS during several weeks of treatment, particularly in old rats. The aim of the present study was first to identify the lowest dose of hexarelin giving maximal stimulation of food intake both in young (3-month-old) and old rats (24-month-old). A dose-response study (80-320 microg/kg, s.c.) revealed that hexarelin at the dose of 80 microg/kg gave reproducibly maximal stimulation of food consumption in young as well as in old rats. Second, we evaluated the effect of 8-week daily sc treatment with hexarelin in young and old male rats. The outcome of the chronic study was that hexarelin (80 microg/kg, s.c., once daily) maintained a persistent significant orexigenic action throughout the treatment period, both in young and old rats. Interestingly, hexarelin treatment did not affect body weight gain either in young or old rats. We conclude that hexarelin is endowed with long-lasting orexigenic activity and might represent a potential therapeutic approach for pathological conditions characterized by a decline in food intake.

Topics: Age Factors; Animals; Appetite; Body Weight; Dose-Response Relationship, Drug; Eating; Feeding Behavior; Growth Substances; Male; Oligopeptides; Rats; Rats, Sprague-Dawley; Weight Gain

The effects of hexarelin, a growth hormone (GH) secretagogue, and human GH on the mechanical and metabolic changes measured in isolated rat hearts submitted to 5 min of Ca2+ deprivation followed by reperfusion with Ca2+-containing medium, the so-called calcium paradox phenomenon, were studied. Hexarelin (80 microg/kg bid, subcutaneously) administered for 7 d to male rats effectively antagonized the sudden increase in resting tension measured in vitro on Ca2+ repletion. Moreover, during Ca2+ repletion the release of creatine kinase activity (an index of cell damage) in the perfusate of these hearts was reduced up to 40% compared with controls. By contrast, administration of hexarelin for 3 d or GH (400 microg/kg bid, subcutaneously) for 7 d did not affect the mechanical and metabolic alterations induced by the calcium paradox. To assess its direct and acute cardiac effects, hexarelin (8 microg/mL) was perfused in vitro in recirculating conditions for 60 min through the hearts of normal rats. In this case, hexarelin did not stimulate heart contractility and failed to prevent ventricular contracture upon Ca2+ readmission, whereas diltiazem, a Ca2+channel blocker, effectively antagonized the calcium paradox phenomenon. We conclude that short-term in vivo exposure to hexarelin, but not GH, enables cardiac myocyites to prevent cytoplasmatic electrolytic unbalance and to control intracellular Ca2+ gain, two functions largely impaired during the calcium paradox phenomenon. Moreover, because the effect of hexarelin is not acute but dependent on the length of in vivo treatment, we suggest that it requires modifications of myocardiocyte physiology.

Topics: Animals; Body Weight; Calcium; Creatine Kinase; Growth Hormone; Heart; Hormones; In Vitro Techniques; Insulin-Like Growth Factor I; Male; Myocardial Contraction; Myocardium; Oligopeptides; Organ Size; Perfusion; Rats; Rats, Sprague-Dawley

Several studies have shown that GH can enhance cardiac performance in rats after experimental myocardial infarction and in humans with congestive heart failure. In the present study, the hemodynamic effects of hexarelin (Hex), an analog of GH-releasing peptide-6 and a potent GH secretagogue, were compared with the effects of GH. Four weeks after ligation of the left coronary artery male rats were treated sc twice daily with hexarelin [10 microg/kg x day (Hex10) or 100 microg/kg x day (Hex100)], recombinant human GH (2.5 mg/kg x day), or 0.9% NaCl for 2 weeks. Transthoracic echocardiography was performed before and after the treatment period. GH, but not Hex, increased body weight gain. GH and Hex100 decreased total peripheral resistance (P < 0.05) and increased stroke volume (P < 0.05 and P < 0.01, respectively) and stroke volume index (P = 0.06 and P < 0.01, respectively) vs. NaCl. Cardiac output was increased by GH and Hex100 (P < 0.05), and cardiac index was increased by Hex100 with a borderline significance for GH (P = 0.06). In conclusion, Hex improves cardiac function and decreases peripheral resistance to a similar extent as exogenous GH in rats postmyocardial infarction. The mechanisms of these effects are unclear; they could be mediated by GH or a direct effect of Hex on the cardiovascular system.

Topics: Animals; Blood Pressure; Body Weight; Echocardiography, Doppler; Electrocardiography; Growth Substances; Heart; Hemodynamics; Humans; In Situ Hybridization; Insulin-Like Growth Factor I; Male; Myocardial Infarction; Myocardium; Oligopeptides; Organ Size; Rats; Rats, Sprague-Dawley; Recombinant Proteins; RNA, Messenger; Vascular Resistance

The endothelial vasodilation mechanism(s) has been investigated in aortic rings of hypophysectomized male rats as well as hypophysectomized rats treated for 7 days with growth hormone (GH, 400 microg/kg, s.c.) or hexarelin (80 microg/kg, s.c.). Tissue preparations from intact animals were taken as controls. The results obtained indicate that the release of 6-keto-prostaglandin F1alpha (6-keto-PGF1alpha) from aortic rings of hypophysectomized rats was markedly reduced (51%; p<0.01) as compared with that of control preparations; the peak response to cumulative concentration of endothelin-1 (ET-1, from 10(-11) to 10(-5) M) was increased 2.4-fold (p<0.01) versus controls; the relaxant activity of acetylcholine (ACh, from 10(-10) to 10(-4) M) in norepinephrine-precontracted aortic rings was reduced by 39.5+/-4.4%. Pretreatment of hypophysectomized rats with GH or hexarelin markedly antagonized the hyperresponsiveness of the aortic tissue to ET-1 and allowed a consistent recovery of both the relaxant activity of ACh and the generation of 6-keto-PGF1alpha. Collectively these findings support the concept that dysfunction of vascular endothelial cells may be induced by a defective GH function. Because a replacement regimen of GH restored the somatotropic function and increased plasma insulin-like growth factor-I (IGF-I) concentrations in the hypophysectomized rats, it is suggested that IGF-I may have protected the vascular endothelium acting as a biologic mediator of GH action. In contrast to GH, hexarelin replacement neither increased body weight nor affected the plasma concentrations of IGF-I, indicating that its beneficial action on vascular endothelium was divorced from that on somatotropic function and was likely due to activation of specific endothelial receptors.

Topics: 6-Ketoprostaglandin F1 alpha; Acetylcholine; Animals; Aorta; Body Weight; Endothelin-1; Endothelium, Vascular; Enzyme Inhibitors; Homeostasis; Human Growth Hormone; Humans; Hypophysectomy; Male; Oligopeptides; omega-N-Methylarginine; Protective Agents; Rats; Rats, Sprague-Dawley; Vasodilation

Hexarelin (Hex) is a synthetic hexapeptide with potent GH-releasing activity in both animals and men. Aim of this study was to evaluate the GH response to a maximal dose of Hex and GH-releasing hormone (GHRH) in a group of patients with Prader-Willi syndrome (PWS). Seven patients (4 boys and 3 girls, age 2.4-14.2 yr) with PWS, 10 prepubertal obese children (7 boys and 3 girls, age 7.5-12.0 yr), and 24 prepubertal short normal children (11 boys and 13 girls, age 5.9-13 yr) with body weight within +/- 10% of their ideal weight were studied. All subjects were tested on two occasions with GHRH 1-29 at the dose of 1 microgram/Kg i.v., and with Hex at the dose of 2 micrograms/Kg i.v. In the PWS patients the GH response to GHRH (peak = 6.4 +/- 2.0 micrograms/l, p < 0.0001; AUC = 248 +/- 70 micrograms min/l, p < 0.0001) was significantly lower than that observed in the short normal children and similar to that observed in the obese children. In the PWS children the GH response to Hex (peak = 7.5 +/- 1.6 micrograms/l; AUC = 309 +/- 53) was similar to that observed after GHRH and significantly lower than that observed in the obese children (p < 0.05). The results of this study show that PWS patients have a blunted GH response to the administration of a maximal dose of Hex. Whether these findings reflect a more severe pituitary GH deficiency in PWS than in obese children or a deranged hypothalamic regulation of GH secretion need further investigation.

Topics: Adolescent; Body Height; Body Mass Index; Body Weight; Child; Child, Preschool; Female; Growth Hormone-Releasing Hormone; Growth Substances; Human Growth Hormone; Humans; Kinetics; Male; Obesity; Oligopeptides; Prader-Willi Syndrome

Male rats were treated with growth hormone (GH)-releasing hormone antiserum to induce selective GH deficiency. The chronic administration of hexarelin to these GH-deficient rats had a pronounced protective effect against ischaemic and post-ischaemic ventricular dysfunction. Hexarelin prevented hyper-responsiveness of the coronary vascular bed to angiotensin II and also prevented the reduction in generation of 6-keto-prostaglandin F1alpha in perfused hearts from GH-deficient rats. The most plausible interpretation of these findings is that hexarelin acts via stimulation of specific cardiac and vascular receptors, triggering currently unknown cytoprotective mechanisms that are responsible for resistance to ischaemic insults and for the preservation of the integrity of the endothelial vasodilation function.

Topics: 6-Ketoprostaglandin F1 alpha; Angiotensin II; Animals; Antibodies; Area Under Curve; Body Weight; Coronary Vessels; Cytoprotection; Endothelium, Vascular; Growth Hormone; Growth Hormone-Releasing Hormone; Heart Ventricles; Male; Myocardial Ischemia; Myocardial Reperfusion; Oligopeptides; Organ Size; Perfusion; Rats; Rats, Sprague-Dawley; Vasoconstrictor Agents; Vasodilation