AUTHOR=Müller Anne , Niederstadt Lars , Jonas Wenke , Yi Chun-Xia , Meyer Franziska , Wiedmer Petra , Fischer Jana , Grötzinger Carsten , Schürmann Annette , Tschöp Matthias , Kleinau Gunnar , Grüters Annette , Krude Heiko , Biebermann Heike TITLE=Ring Finger Protein 11 Inhibits Melanocortin 3 and 4 Receptor Signaling JOURNAL=Frontiers in Endocrinology VOLUME=7 YEAR=2016 URL=https://www.frontiersin.org/journals/endocrinology/articles/10.3389/fendo.2016.00109 DOI=10.3389/fendo.2016.00109 ISSN=1664-2392 ABSTRACT=

Intact melanocortin signaling via the G protein-coupled receptors (GPCRs), melanocortin receptor 4 (MC4R), and melanocortin receptor 3 (MC3R) is crucial for body weight maintenance. So far, no connection between melanocortin signaling and hypothalamic inflammation has been reported. Using a bimolecular fluorescence complementation library screen, we identified a new interaction partner for these receptors, ring finger protein 11 (RNF11). RNF11 participates in the constitution of the A20 complex that is involved in reduction of tumor necrosis factor α (TNFα)-induced NFκB signaling, an important pathway in hypothalamic inflammation. Mice treated with high-fat diet (HFD) for 3 days demonstrated a trend toward an increase in hypothalamic Rnf11 expression, as shown for other inflammatory markers under HFD. Furthermore, Gs-mediated signaling of MC3/4R was demonstrated to be strongly reduced to 20–40% by co-expression of RNF11 despite unchanged total receptor expression. Cell surface expression was not affected for MC3R but resulted in a significant reduction of MC4R to 61% by co-expression with RNF11. Mechanisms linking HFD, inflammation, and metabolism remain partially understood. In this study, a new axis between signaling of specific body weight regulating GPCRs and factors involved in hypothalamic inflammation is suggested.