Small-Molecule Ghrelin Receptor Antagonists Improve Glucose Tolerance, Suppress Appetite, and Promote Weight Loss (original) (raw)
Related papers
European Journal of Pharmacology, 2009
Here we provide the first pharmacological exploration of the impact of acute central nervous system exposure to three recently developed ghrelin receptor (GHS-R1A) ligands on food intake and on the electrical activity of the target cells for ghrelin in the hypothalamus. Central (i.c.v) injection of GHS-R1A antagonists to rats suppressed food intake induced by i.c.v ghrelin injection (1 μg) in a dose-dependent manner with a total blockade at concentrations of 0.4 μg and 8 μg for JMV 3002 and JMV 2959 respectively. JMV 2810, a partial agonist, also suppressed ghrelin-induced food intake (range: 0.02-2 μg). Moreover all three compounds reduced fasting-induced food intake in rats (i.e. the amount of food eaten during the first hour of food exposure after a 16 h fast). At the single cell level we also explored the effects of the compounds to suppress ghrelin (0.5 μM)-induced changes in electrical activity of arcuate nucleus cells recorded extracellularly in a slice preparation. Preincubation followed by perfusion with the GHS-R1A ligands suppressed the responsiveness of arcuate cells to ghrelin. Thus, the recently developed GHS-R1A ligands (JMV 3002, 2959 and 2810) suppress ghrelin-induced and fasting-induced food intake at the level of the central nervous system. This appears to be mediated, at least in part, by a modulation of the activity of ghrelin-responsive arcuate nucleus cells. As the central ghrelin signalling system has emerged as an important pro-obesity target, it will be important to establish the efficacy of these GHS-R1A ligands to reduce fat mass in clinical studies.
Effect of Ghrelin Antagonist on Food and Water Intake in Obese and Type 2 Diabetic Mice
2017
Background: Ghrelin is the most common orexigenic hormone which acts as starvation signal by acting on hypothalamic neurons. It acts as adipogenic agent. Increased food intake caused by high levels of ghrelin causes increase fat mass. We investigated the possible beneficial role of ghrelin antagonist on food and water intake in obese and type 2 diabetic mice. Methods: This study was carried out at Department of Physiology, Army Medical College, Rawalpindi in collaboration with National Institute of Health, Islamabad, from Jan to Jun 2013. A total of 50 healthy male BALB/c mice were divided into 5 groups. Group I served as control, groups II and III were obese, and group IV and V were diabetic. Group II, III, IV and V were fed high-fat diet for 4 weeks. Group IV and V were given intraperitoneal (IP) injection of streptozotocin to induce type 2 diabetes mellitus. Ghrelin antagonist was injected IP to Group III and V for 6 days. Food and water intake were measured daily. Body weights w...
Are we at the verge of finding a new efficacious pharmacotherapy for obesity in the form of agonism at triple drug receptors: glucagon, Glucagon like peptide1 (GLP1), glucose dependent insulin tropic peptide (GIP), 2019
Obesity is becoming a worldwide pandemic, and it calls for concerted efforts to act in view of preventing it from becoming a menace. Since lifestyle interventions and exercise have proven to be not of much use by themselves with the weight loss getting defended by the obese brain, with the regained weight set point gets defended. Currently most pharmacotherapy do not offer a sustained weight loss and don’t have efficacy over 1-5kg loss for over 3-6mths.Till now the only drug having some promise are believed to be thylakoids. Although the most effective weight loss strategy remains bariatric surgery(BS),although its mechanism of action remains unclear though it is the most effective ,but indicated in limited cases with severe morbidly obese or those with BMI over 35kg with co morbidities. Further it has disadvantage of being costly and not available to all obese patients and is not without its inherent risks .Still it causes immediate remission of T2DM,and mediates sustained weight loss .Some proposed mechanism of action of BS is by acting through CNS and some other GIT hormones like GLP1, ghrelin PYY. Thus the new class of multiagonists drugs are trying to combine to form a single molecular drug which might try to close the gap, improving efficacy to improve the metabolism of the system. The drug constitutes a single drug in which agonism for the receptors of glucagon, glucagon like peptide1 (GLP1), glucose dependent insulunotropic polypeptide (GIP) is combined. In preclinical studies these multiagonists do better than their mono agonist counter parts. In clinical trials rigorous safety analysis are on the way and these drugs might be on the way in becoming the elusive pharmacotherapy for obesity. Currently the drugs offering most promise as medical therapies remain thylakoids, BAT directed therapies and with these drugs passing the test of time and human clinical trials might be the most superior multiagonists for the future hopefully. Keywords: BS; Glp1;GIP, Glucagon Dual and Triple Agonists; obesity; weight loss
Novel -MSH analog causes weight loss in obese rats and minipigs and improves insulin sensitivity
Journal of Endocrinology, 2014
Obesity is a major burden to people and to health care systems around the world. The aim of the study was to characterize the effect of a novel selective a-MSH analog on obesity and insulin sensitivity. The subchronic effects of the selective MC4-R peptide agonist MC4-NN1-0182 were investigated in diet-induced obese (DIO) rats and DIO minipigs by assessing the effects on food intake, energy consumption, and body weight. The acute effect of MC4-NN1-0182 on insulin sensitivity was assessed by a euglycemic-hyperinsulinemic clamp study in normal rats. Three weeks of treatment of DIO rats with MC4-NN1-0182 caused a decrease in food intake and a significant decrease in body weight 7G1%, P!0.05 compared with 3G1% increase with the vehicle control. In DIO minipigs, 8 weeks of treatment with MC4-NN1-0182 resulted in a body weight loss of 13.3G2.5 kg (13G3%), whereas the vehicle control group had gained 3.7G1.4 kg (4G1%). Finally, clamp studies in normal rats showed that acute treatment with MC4-NN1-0182 caused a significant increase in glucose disposal (Rd) compared with vehicle control (Rd, mg/kg per min, 17.0G0.7 vs 13.9G0.6, P!0.01). We demonstrate that treatment of DIO rats or minipigs with a selective MC4-R peptide agonist causes weight loss. Moreover, we have demonstrated weightindependent effects on insulin sensitivity. Our observations identify MC4 agonism as a viable target for the treatment of obesity and insulin resistance. Key Words " obesity " insulin resistance " hyperinsulinemic-euglycemic clamp " melanocortin receptor 4 " agonist " ISI Journal of Endocrinology (2014) 220, 97-107 Journal of Endocrinology Research Open Access K FOSGERAU and others a-MSH analog improves insulin sensitivity 220:2 97-107 Journal of Endocrinology Research K FOSGERAU and others a-MSH analog improves insulin sensitivity 220:2 98 Journal of Endocrinology Research K FOSGERAU and others a-MSH analog improves insulin sensitivity 220:2 99 Journal of Endocrinology Research K FOSGERAU and others a-MSH analog improves insulin sensitivity 220:2 101 Journal of Endocrinology Research K FOSGERAU and others a-MSH analog improves insulin sensitivity 220:2 103 GS.E.M., nZ6/group. Rats treated with MC4-NN1-0182 were compared with vehicle control using an unpaired Student's t-test where ** indicates P!0.01 vs vehicle control.
2009
OBJECTIVE-Oxyntomodulin (OXM) is a glucagon-like peptide 1 (GLP-1) receptor (GLP1R)/glucagon receptor (GCGR) dual agonist peptide that reduces body weight in obese subjects through increased energy expenditure and decreased energy intake. The metabolic effects of OXM have been attributed primarily to GLP1R agonism. We examined whether a long acting GLP1R/GCGR dual agonist peptide exerts metabolic effects in diet-induced obese mice that are distinct from those obtained with a GLP1R-selective agonist. RESEARCH DESIGN AND METHODS-We developed a protease-resistant dual GLP1R/GCGR agonist, DualAG, and a corresponding GLP1R-selective agonist, GLPAG, matched for GLP1R agonist potency and pharmacokinetics. The metabolic effects of these two peptides with respect to weight loss, caloric reduction, glucose control, and lipid lowering, were compared upon chronic dosing in diet-induced obese (DIO) mice. Acute studies in DIO mice revealed metabolic pathways that were modulated independent of weight loss. Studies in Glp1r Ϫ/Ϫ and Gcgr Ϫ/Ϫ mice enabled delineation of the contribution of GLP1R versus GCGR activation to the pharmacology of DualAG. RESULTS-Peptide DualAG exhibits superior weight loss, lipidlowering activity, and antihyperglycemic efficacy comparable to GLPAG. Improvements in plasma metabolic parameters including insulin, leptin, and adiponectin were more pronounced upon chronic treatment with DualAG than with GLPAG. Dual receptor agonism also increased fatty acid oxidation and reduced hepatic steatosis in DIO mice. The antiobesity effects of DualAG require activation of both GLP1R and GCGR. CONCLUSIONS-Sustained GLP1R/GCGR dual agonism reverses obesity in DIO mice and is a novel therapeutic approach to the treatment of obesity. Diabetes 58:2258-2266, 2009 O besity is an important risk factor for type 2 diabetes, and ϳ90% of patients with type 2 diabetes are overweight or obese (1). Among new therapies for type 2 diabetes, peptidyl mimetics of the gut-derived incretin hormone glucagonlike peptide 1 (GLP-1) stimulate insulin biosynthesis and From the
2013
The stimulatory effects of ghrelin, a 28-AA acylated peptide originally isolated from stomach, on growth hormone (GH) secretion and feeding are exclusively mediated through the growth hormone secretagogue 1a receptor (GHS-R1a), the only ghrelin receptor described so far. Several GHS-R1a agonists and antagonists have been developed to treat metabolic or nutritional disorders but their mechanisms of action in the central nervous system remain poorly understood. In the present study, we compared the activity of BIM-28163, a GHS-R1a antagonist, and of several agonists, including native ghrelin and the potent synthetic agonist, BIM-28131, to modulate food intake, GH secretion, and cFos activity in arcuate nucleus (ArcN), nucleus tractus solitarius (NTS), and area postrema (AP) in wild-type and NPY-GFP mice. BIM-28131 was as effective as ghrelin in stimulating GH secretion, but more active than ghrelin in inducing feeding. It stimulated cFos activity similarly to ghrelin in the NTS and AP but was more powerful in the ArcN, suggesting that the super-agonist activity of BIM-28131 is mostly mediated in the ArcN. BIM-28163 antagonized ghrelin-induced GH secretion but not ghrelin-induced food consumption and cFos activation, rather it stimulated food intake and cFos activity without affecting GH secretion.The level of cFos activation was dependent on the region considered: BIM-28163 was as active as ghrelin in the NTS, but less active in the ArcN and AP. All compounds also induced cFos immunoreactivity in ArcN NPY neurons but BIM-28131 was the most active. In conclusion, these data demonstrate that two peptide analogs of ghrelin, BIM-28163, and BIM-28131, are powerful stimulators of appetite in mice, acting through pathways and key brain regions involved in the control of appetite that are only partially superimposable from those activated by ghrelin. A better understanding of the molecular pathways activated by these compounds could be useful in devising future therapeutic applications, such as for cachexia and anorexia.
Journal of Pharmacology and Experimental Therapeutics, 2011
Pharmacologic contributions of directly agonizing glucagonlike peptide 1 (GLP-1) receptor or antagonizing glucagon receptor (GCGR) on energy state and glucose homeostasis were assessed in diet-induced obese (DIO) mice. Metabolic rate and respiratory quotient (RQ), hyperglycemic clamp, stable isotopebased dynamic metabolic profiling (SiDMAP) studies of 13 Clabeled glucose during glucose tolerance test (GTT) and gene expression were assessed in cohorts of DIO mice after a single administration of GLP-1 analog [GLP-1-(23)] or anti-GCGR antibody (Ab). GLP-1-(23) and GCGR Ab similarly improved GTT. GLP-1-(23) decreased food intake and body weight trended lower. GCGR Ab modestly decreased food intake without significant effect on body weight. GLP-1-(23) and GCGR Ab decreased RQ with GLP-1, causing a greater effect. In a hyperglycemic clamp, GLP-1-(23) reduced hepatic glucose production (HGP), increased glucose infusion rate (GIR), increased glucose uptake in brown adipose tissue, and increased whole-body glucose turnover, glycolysis, and rate of glycogen synthesis. GCGR Ab slightly decreased HGP, increased GIR, and increased glucose uptake in the heart. SiDMAP showed that GLP-1-(23) and GCGR Ab increased 13 C lactate labeling from glucose, indicating that liver, muscle, and other organs were involved in the rapid disposal of glucose from plasma. GCGR Ab and GLP-1-(23) caused different changes in mRNA expression levels of glucose-and lipid metabolism-associated genes. The effect of GLP-1-(23) on energy state and glucose homeostasis was greater than GCGR Ab. Although GCGR antagonism is associated with increased circulating levels of GLP-1, most GLP-1-(23)-associated pharmacologic effects are more pronounced than GCGR Ab.
Glucagon-Like Peptide 1/Glucagon Receptor Dual Agonism Reverses Obesity in Mice
Diabetes, 2009
OBJECTIVE-Oxyntomodulin (OXM) is a glucagon-like peptide 1 (GLP-1) receptor (GLP1R)/glucagon receptor (GCGR) dual agonist peptide that reduces body weight in obese subjects through increased energy expenditure and decreased energy intake. The metabolic effects of OXM have been attributed primarily to GLP1R agonism. We examined whether a long acting GLP1R/GCGR dual agonist peptide exerts metabolic effects in diet-induced obese mice that are distinct from those obtained with a GLP1R-selective agonist.