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Ghrelin receptor inverse agonists as a novel therapeutic approach against obesity‐related metabolic disease
Author(s) -
Abegg Kathrin,
Bernasconi Lara,
Hutter Melanie,
Whiting Lynda,
Pietra Claudio,
Giuliano Claudio,
Lutz Thomas A.,
Riediger Thomas
Publication year - 2017
Publication title -
diabetes, obesity and metabolism
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.445
H-Index - 128
eISSN - 1463-1326
pISSN - 1462-8902
DOI - 10.1111/dom.13020
Subject(s) - ghrelin , medicine , endocrinology , diet induced obese , inverse agonist , glucose homeostasis , receptor , energy homeostasis , diabetes mellitus , insulin resistance , agonist
Aims Ghrelin is implicated in the control of energy balance and glucose homeostasis. The ghrelin receptor exhibits ligand‐independent constitutive activity, which can be pharmacologically exploited to induce inverse ghrelin actions. Because ghrelin receptor inverse agonists ( GHSR ‐ IA ) might be effective for the treatment of obesity‐related metabolic disease, we tested 2 novel synthetic compounds GHSR ‐ IA 1 and GHSR ‐ IA 2. Materials and Methods In functional cell assays, electrophysiogical and immunohistochemical experiments, we demonstrated inverse agonist activity for GHSR ‐ IA 1 and GHSR ‐ IA 2. We used healthy mice, Zucker diabetic fatty ( ZDF ) rats and diet‐induced obese ( DIO ) mice to explore effects on food intake ( FI ), body weight ( BW ), conditioned taste aversion ( CTA ), oral glucose tolerance ( OGT ), pancreatic islet morphology, hepatic steatosis ( HS ), and blood lipids. Results Both compounds acutely reduced FI in mice without inducing CTA . Chronic GHSR ‐ IA 1 increased metabolic rate in chow‐fed mice, suppressed FI , and improved OGT in ZDF rats. Moreover, the progression of islet hyperplasia to fibrosis in ZDF rats slowed down. GHSR ‐ IA 2 reduced FI and BW in DIO mice, and reduced fasting and stimulated glucose levels compared with pair‐fed and vehicle‐treated mice. GHSR ‐ IA 2‐treated DIO mice showed decreased blood lipids. GHSR ‐ IA 1 treatment markedly decreased HS in DIO mice. Conclusions Our study demonstrates therapeutic actions of novel ghrelin receptor inverse agonists, suggesting a potential to treat obesity‐related metabolic disorders including diabetes mellitus.