Long-term treatment with the ghrelin receptor antagonist [<scp>d</scp>-Lys3]-GHRP-6 does not improve glucose homeostasis in nonobese diabetic MKR mice

Mosa, Rasha; Huang, Lili; Li, Hongzhuo; Grist, Michael; LeRoith, Derek; Chen, Chen

doi:10.1152/ajpregu.00157.2017

Cited by 16 publications

(5 citation statements)

References 54 publications

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“…As increases in circulating ghrelin levels leads to increased hunger, rather than treatment with the hormone itself, research is focusing on ghrelin receptor antagonists which would block ghrelin receptors to reduce hunger signalling. However, the results from research on animal models has produced mixed results thus far [ 118 , 119 , 120 ]. Another possible therapy being examined is oral CCK receptor agonists [ 121 ], CCK receptor agonists are used as administration of CCK itself has been found to cause nausea when administered over long periods [ 93 ].…”

Section: Gut Hormones In the Treatment Of Obesitymentioning

confidence: 99%

Gut Hormones in Health and Obesity: The Upcoming Role of Short Chain Fatty Acids

et al. 2021

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We are currently facing an obesity pandemic, with worldwide obesity rates having tripled since 1975. Obesity is one of the main risk factors for the development of non-communicable diseases, which are now the leading cause of death worldwide. This calls for urgent action towards understanding the underlying mechanisms behind the development of obesity as well as developing more effective treatments and interventions. Appetite is carefully regulated in humans via the interaction between the central nervous system and peripheral hormones. This involves a delicate balance in external stimuli, circulating satiating and appetite stimulating hormones, and correct functioning of neuronal signals. Any changes in this equilibrium can lead to an imbalance in energy intake versus expenditure, which often leads to overeating, and potentially weight gain resulting in overweight or obesity. Several lines of research have shown imbalances in gut hormones are found in those who are overweight or obese, which may be contributing to their condition. Therefore, this review examines the evidence for targeting gut hormones in the treatment of obesity by discussing how their dysregulation influences food intake, the potential possibility of altering the circulating levels of these hormones for treating obesity, as well as the role of short chain fatty acids and protein as novel treatments.

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Section: Gut Hormones In the Treatment Of Obesitymentioning

confidence: 99%

Gut Hormones in Health and Obesity: The Upcoming Role of Short Chain Fatty Acids

et al. 2021

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“…The ligand JMV2959 has also been demonstrated to be unable to inhibit GH secretion produced by hexarelin but to suppress food intake at the same time (77). In addition, it has been shown that Dlys reduces pulsatile GH secretion and body fat mass, but worsens glucose and insulin intolerance and increases cumulative food intake (78). How are these physiologic responses connected to functional bias signaling of GHSR-1a?…”

Section: Mk0677 (Nm)mentioning

confidence: 99%

Differential functional selectivity and downstream signaling bias of ghrelin receptor antagonists and inverse agonists

et al. 2018

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The ghrelin receptor [growth hormone secretagogue receptor (GHSR)‐1a] represents a promising pharmacologic target for the treatment of metabolic disorders, including obesity and cachexia, via central appetite modulation. The GHSR‐1a has a complex pharmacology, highlighted by G‐protein–dependent and—independent downstream signaling pathways and high basal constitutive activity. The functional selectivity and signaling bias of many GHSR‐1a–specific ligands has not been fully characterized. In this study, we investigated the pharmacologic properties of ghrelin, MK‐0677, L692,585, and [d‐Lys3]‐growth hormone–releasing peptide‐6 (Dlys), JMV2959, and [d‐Arg(1),d‐Phe(5),d‐Trp(7, 9), Leu(11)]‐substance P (SP‐analog). We investigated their effect on basal GHSR‐1a constitutive signaling, ligand‐directed downstream GHSR‐1a signaling, functional selectivity, and signaling bias. Dlys behaved as a partial antagonist with a strong bias toward GHSR‐1a–β‐arrestin signaling, whereas JMV2959 acted as a full unbiased GHSR‐1a antagonist. Moreover, the SP‐analog behaved as an inverse agonist increasing G‐protein–dependent signaling, but only at high concentrations, whereas, at low concentrations, the SP‐analog attenuated β‐arrestin–dependent signaling. Considering the limited success in the clinical development of GHSR‐1a–targeted drugs so far, these findings provide a novel insight into the pharmacologic characteristics of GHSR‐1a ligands and their signaling bias, which has important implications in the design of novel, more selective GHSR‐1a ligands with predictable functional outcome and selectivity for preclinical and clinical drug development.—Ramirez, V. T., van Oeffelen, W. E. P. A., Torres‐Fuentes, C., Chruścicka, B., Druelle, C., Golubeva, A. V., van de Wouw, M., Dinan, T. G., Cryan, J. F., Schellekens, H. Differential functional selectivity and downstream signaling bias of ghrelin receptor antagonists and inverse agonists. FASEB J. 33, 518–531 (2019). http://www.fasebj.org

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“…We were surprised by the impaired glucose tolerance and reduced insulin levels induced by GRA in WT ferrets, especially given that ghrelin antagonists do not worsen insulin secretion or glucose tolerance in a variety of non-diabetic mouse models.. However, this finding is not without precedent, as GHSR antagonist worsens insulin secretion in fed sheep [33], causes hyperglycemia in some rodent models [34] and ablation of GHSR in ob/ob mice worsens hyperglycemia and reduces insulin secretion [35]. The ultimate effect of acyl-ghrelin actions on beta cell insulin secretion will depend on the relative balance of somatostatin, GHSR, and GLP-1 tone.…”

Section: Discussionmentioning

confidence: 99%

Incretin dysfunction and hyperglycemia in cystic fibrosis: Role of acyl-ghrelin

Sun

Liang

et al. 2019

Journal of Cystic Fibrosis

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Background: Insulin secretion is insufficient in cystic fibrosis (CF), even before diabetes is present, though the mechanisms involved remain unclear. Acyl-ghrelin (AG) can diminish insulin secretion and is elevated in humans with CF. Methods: We tested the hypothesis that elevated AG contributes to reduced insulin secretion and hyperglycemia in CF ferrets. Results: Fasting AG was elevated in CF versus non-CF ferrets. Similar to its effects in other species, AG administration in non-CF ferrets acutely reduced insulin, increased growth hormone, and induced hyperglycemia. During oral glucose tolerance testing, non-CF ferrets had responsive insulin, glucagon like peptide-1 (GLP-1) and gastric inhibitory polypeptide (GIP) levels and maintained normal glucose levels, whereas CF ferrets had insufficient responses and became hyperglycemic. Interestingly in wild-type ferrets, the acyl-ghrelin receptor antagonist [D-Lys3]-GHRP-6 impaired glucose tolerance, and abolished insulin, GLP-1, and GIP responses during glucose tolerance testing. By contrast, in CF ferrets [D-Lys3]-GHRP-6 improved glucose tolerance, enhanced the insulin-to-glucose ratio, but did not impact the already low GLP-1 and GIP levels. Conclusions: These results suggest a mechanism by which elevated AG contributes to CF hyperglycemia through inhibition of insulin secretion, an effect magnified by low GLP-1 and GIP. Interventions that lower ghrelin, ghrelin action, and/or raise GLP-1 or GIP might improve glycemia in CF.

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Long-term treatment with the ghrelin receptor antagonist [d-Lys3]-GHRP-6 does not improve glucose homeostasis in nonobese diabetic MKR mice

Cited by 16 publications

References 54 publications

Gut Hormones in Health and Obesity: The Upcoming Role of Short Chain Fatty Acids

Gut Hormones in Health and Obesity: The Upcoming Role of Short Chain Fatty Acids

Differential functional selectivity and downstream signaling bias of ghrelin receptor antagonists and inverse agonists

Incretin dysfunction and hyperglycemia in cystic fibrosis: Role of acyl-ghrelin

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