ECE2016 Eposter Presentations Obesity (69 abstracts)
Glucose transporter 1 suppresses melanocortin 4 receptor activity
Anne Müller 1 , Lars Niederstadt 2 , Sabine Jyrch 1 , Wenke Jonas 3, , Franziska Meyer 5 , Carsten Grötzinger 2 , Annette Schürmann 3, , Gunnar Kleinau 1 , Annette Grüters 1 , Heiko Krude 1 & Heike Biebermann 1
1Institut für Experimentelle Pädiatrische Endokrinologie, Charité-Universitätsmedizin, Berlin, Germany; 2Department of Hepatology and Gastroenterology and Molecular Cancer Research Center (MKFZ), Tumor Targeting Lab, Charité-Universitätsmedizin, Berlin, Germany; 3Department of Experimental Diabetology, German Institute of Human Nutrition (DIfE), Potsdam-Rehbruecke, Germany; 4German Center of Diabetes Research, Neuherberg, Germany; 5Institut für Experimentelle Endokrinologie, Charité-Universitätsmedizin, Berlin, Germany.
The melanocortin 4 receptor (MC4R) represents the major hypothalamic G-protein coupled receptor (GPCR) controlling feeding behavior and therefore body weight regulation. MC4R is highly expressed in the paraventricular nucleus (PVN) where hormonal and neuroendocrine signals from periphery and arcuate nucleus (ARC) are allocated. MC4R knockout in mice or natural occurring loss-of function variants result in hyperphagia and early-onset obesity. MC4R mutations represent the most frequent genetic cause for human obesity. Over the last years there is growing evidence that GPCRs tend to interact with other GPCRs or non-GPCR proteins. Analyzing a possible MC4R protein network by screening for new interaction partners, we found the glucose transporter 1 (GLUT1) to be a possible MC4R interacting partner. By immunohistochemistry we could demonstrate expression of GLUT1 on PVN neurons. Moreover, co-expression of GLUT1 and MC4R on different murine neuronal cell-lines could be shown, indicating a theoretical possibility that both proteins interact. Using two different assay systems, we furthermore could affirm a direct GLUT1/MC4R interaction. Functional studies revealed strong down-regulation of alpha-MSH mediated MC4R signaling by GLUT1 co-expression. As a possible mechanism, we identified a reduction in cell surface expression of MC4R due to GLUT1 co-expression. Uptake studies revealed that the MC4R itself has an impact on cellular glucose feed-in augmenting our hypothesis of a veritable connection between glucose sensing and MC4R signaling. Finally, gene expression analyses showed strong down-regulation of Glut1 after three days of high-fat diet. Therefore, nutritional reduction of GLUT1 might increase MC4R action in controlling food intake.
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Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
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