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Wiedemann, T. ; Bielohuby, M.* ; Müller, T.D. ; Bidlingmaier, M.* ; Pellegata, N.S.

Obesity in MENX rats is accompanied by high circulating levels of ghrelin and improved insulin sensitivity.

Diabetes 65, 406-420 (2015)
DOI PMC
Open Access Green as soon as Postprint is submitted to ZB.
Ghrelin, the natural ligand of the growth hormone secretagogue receptor (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 epsilon 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 (GSIS) in MENX rats while insulin sensitivity is improved. In summary, we provide a novel, non-transgenic 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.
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Publication type Article: Journal article
Document type Scientific Article
Corresponding Author
Keywords Multiple Endocrine Neoplasia; Agouti-related Protein; Lipid-accumulation; Pancreatic-islets; Acylated Peptide; Neuropeptide-y; Messenger-rna; Beta-cells; Hormone; Humans
ISSN (print) / ISBN 0012-1797
e-ISSN 1939-327X
Journal Diabetes
Quellenangaben Volume: 65, Issue: 2, Pages: 406-420 Article Number: , Supplement: ,
Publisher American Diabetes Association
Publishing Place Alexandria, VA.
Non-patent literature Publications
Reviewing status Peer reviewed
Institute(s) Institute of Pathology (PATH)
Institute of Diabetes and Obesity (IDO)