title: Obesity in MENX Rats Is Accompanied by High Circulating Levels of Ghrelin and Improved Insulin Sensitivity.
abstract: Ghrelin, the natural ligand of the growth hormone secretagogue receptor type 1a (GHS-R1a), is mainly secreted from the stomach and regulates food intake and energy homeostasis. p27 regulates cell cycle progression in many cell types. Here, we report that rats affected by the multiple endocrine neoplasia syndrome MENX, caused by a p27 mutation, develop pancreatic islet hyperplasia containing elevated numbers of ghrelin-producing ε-cells. The metabolic phenotype of MENX-affected rats featured high endogenous acylated and unacylated plasma ghrelin levels. Supporting increased ghrelin action, MENX rats show increased food intake, enhanced body fat mass, and elevated plasma levels of triglycerides and cholesterol. Ghrelin effect on food intake was confirmed by treating MENX rats with a GHS-R1a antagonist. At 7.5 months, MENX-affected rats show decreased mRNA levels of hypothalamic GHS-R1a, neuropeptide Y (NPY), and agouti-related protein (AgRP), suggesting that prolonged hyperghrelinemia may lead to decreased ghrelin efficacy. In line with ghrelin's proposed role in glucose metabolism, we find decreased glucose-stimulated insulin secretion in MENX rats, while insulin sensitivity is improved. In summary, we provide a novel nontransgenic rat model with high endogenous ghrelin plasma levels and, interestingly, improved glucose tolerance. This model might aid in identifying new therapeutic approaches for obesity and obesity-related diseases, including type 2 diabetes.
authors.affiliation: Institute of Pathology, Helmholtz Center Munich, German Research Center for Environmental Health, Technical University Munich, Munich, Germany.
authors.forename: Tobias
authors.initials: T
authors.lastname: Wiedemann
authors.affiliation: Endocrine Research Unit, Medizinische Klinik und Poliklinik IV, Klinikum der Universität, Ludwigs-Maximilians University, Munich, Germany.
authors.forename: Maximilian
authors.initials: M
authors.lastname: Bielohuby
authors.affiliation: Institute for Diabetes and Obesity, Helmholtz Center Munich, German Research Center for Environmental Health, Technical University Munich, Munich, Germany.
authors.forename: Timo D
authors.initials: TD
authors.lastname: Müller
authors.affiliation: Endocrine Research Unit, Medizinische Klinik und Poliklinik IV, Klinikum der Universität, Ludwigs-Maximilians University, Munich, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Bidlingmaier
authors.affiliation: Institute of Pathology, Helmholtz Center Munich, German Research Center for Environmental Health, Technical University Munich, Munich, Germany natalia.pellegata@helmholtz-muenchen.de.
authors.forename: Natalia S
authors.initials: NS
authors.lastname: Pellegata
mesh_terms: D054369:Agouti-Related Protein / Q000378:metabolism; D000818:Animals; D001069:Appetite Regulation / Q000187:drug effects / Q000502:physiology; D001786:Blood Glucose / Q000378:metabolism; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000235:genetics; D054439:Ghrelin / Q000097:blood*; D007031:Hypothalamus / Q000378:metabolism; D007333:Insulin Resistance / Q000502:physiology*; D009377:Multiple Endocrine Neoplasia / Q000097:blood* / Q000150:complications / Q000235:genetics; D009154:Mutation; D009478:Neuropeptide Y / Q000378:metabolism; D009765:Obesity / Q000097:blood* / Q000150:complications; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D054440:Receptors, Ghrelin / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000627:therapeutic use
chemical_list: C515197:AGRP protein, rat; D054369:Agouti-Related Protein; D001786:Blood Glucose; C493962:Cdkn1b protein, rat; D054439:Ghrelin; C571124:Ghsr1a protein, rat; D009478:Neuropeptide Y; D012333:RNA, Messenger; D054440:Receptors, Ghrelin; D050760:Cyclin-Dependent Kinase Inhibitor p27