Ghrelin receptor inverse agonists as a novel therapeutic approach against obesity-related metabolic disease

Autor: Melanie Hutter, Lara Bernasconi, Claudio Pietra, Thomas A. Lutz, Thomas Riediger, Kathrin Abegg, Claudio Giuliano, Lynda Whiting
Přispěvatelé: University of Zurich, Riediger, Thomas
Rok vydání: 2017
Předmět:
0301 basic medicine
Endocrinology
Diabetes and Metabolism
Blood lipids
Weight Gain
Mice
Random Allocation
0302 clinical medicine
Endocrinology
Non-alcoholic Fatty Liver Disease
Glucose homeostasis
Receptor
Receptors
Ghrelin
Neurons
geography.geographical_feature_category
digestive
oral
and skin physiology
Islet
10081 Institute of Veterinary Physiology
1310 Endocrinology
2712 Endocrinology
Diabetes and Metabolism
Liver
10076 Center for Integrative Human Physiology
Ghrelin
medicine.medical_specialty
Drug Inverse Agonism
030209 endocrinology & metabolism
Hyperlipidemias
Diet
High-Fat
03 medical and health sciences
Islets of Langerhans
Internal medicine
Diabetes mellitus
Internal Medicine
medicine
Inverse agonist
Animals
Humans
Hypoglycemic Agents
Obesity
geography
business.industry
Arcuate Nucleus of Hypothalamus
medicine.disease
Rats
Rats
Zucker
030104 developmental biology
HEK293 Cells
Diabetes Mellitus
Type 2
2724 Internal Medicine
570 Life sciences
biology
Anti-Obesity Agents
Steatosis
business
Energy Intake
Zdroj: Diabetes, obesitymetabolism. 19(12)
ISSN: 1463-1326
Popis: 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. Since ghrelin receptor inverse agonists (GHSR-IA) might be effective for the treatment of obesity-related metabolic disease, we tested two novel synthetic compounds GHSR-IA1 and GHSR-IA2. Materials and methods In functional cell assays, electrophysiogical and immunohistochemical experiments, we demonstrated inverse agonist activity for GHSR-IA1 and GHSR-IA2. We used healthy mice, Zucker diabetic fatty (ZDF) rats and diet-induced obese mice (DIO) 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-IA1 increased metabolic rate (MR) 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-IA2 reduced FI and BW in DIO mice and reduced fasting and stimulated glucose levels compared to pair-fed and vehicle-treated mice. GHSR-IA2-treated DIO mice showed decreased blood lipids. GHSR-IA1 treatment markedly decreased HS in DIO mice. Conclusions Our study demonstrates therapeutic actions of novel ghrelin receptor inverse agonists suggesting a possible potential to treat obesity-related metabolic disorders including diabetes mellitus.
Databáze: OpenAIRE
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