ESPE2023 Free Communications Fat, metabolism and obesity 1 (6 abstracts)
Analysis of ligand- and mutation-dependent signaling of the melanocortin 4 receptor (MC4R): an example of the relevance of differential signaling (bias signaling)
Lisa Ruck 1 , Sarah Paisdzior 2 , Patrick Scheerer 3 , Susanna Wiegand 1 , Gunnar Kleinau 3 , Nicolas A. Heyder 3 , Annette G. Beck-Sickinger 4 , Manuel C. Troll 4 , Heike Biebermann 2 & Peter Kühnen 2
1Clinic for Pediatric Endocrinology, Charité Universitätsmedizin, Berlin, Germany. 2Institute of Experimental Pediatric Endocrinology, Charité Universitätsmedizin, Berlin, Germany. 3Institut of Medical Physics and Biophysics, Charité Universitätsmedizin, Berlin, Germany. 4Institut of Biochemistry, Universität Leipzig, Leipzig, Germany
Introduction: The melanocortin 4 receptor (MC4R) is a G protein coupled receptor (GPCR) and plays a pivotal role in the central regulation of body weight in the hypothalamus. In the context of the leptin-melanocortin signaling pathway, the MC4R is activated by the endogenous ligands a- and b-MSH (melanocyte-stimulating hormone). This leads to the feeling of satiety and to a reduction in food intake. Mutations within the genes leptin, leptin receptor (LEPR), pro-opiomelanocortin (POMC) and MC4R lead to a functional impairment of the leptin-melanocortin signaling pathway and thus to hyperphagia and the development of early-onset obesity. Recently, the MC4R agonist setmelanotide was approved as a drug therapy for patients with homozygous mutations in the LEPR and POMC genes. Initial studies indicate that the effect of setmelanotide is particularly due to a change in MC4R signaling (differential signaling). For this reason, the aim of this investigations was to determine the extent to which ligands such as setmelanotide and mutations in the MC4R gene alter the signaling profile of the MC4R.
Methods: 10 MC4R mutations associated with the development of obesity were investigated in vitro in HEK293 cells. After transfection and expression of wild-type MC4R and MC4R mutations, four different signaling pathways (Gs, Gq/11, ERK, G12/13), b-arrestin2 recruitment, as well as surface expression were examined after stimulation with three different ligands (a-MSH, b-MSH, setmelanotide). Additionally, the mutations were structurally characterized based on the cryo-electron microscopic (cyro-EM) structure of MC4R.
Results: The investigated MC4R mutations affected the signaling profile of the MC4R in different ways. Also, stimulation with certain ligands led to a change in differential signaling. We were able to show that a mutated and therefore disturbed MC4R signaling pathway could be restored after stimulation with specific ligands. These observations can be explained by changes in the MC4R structure.
Conclusion: The results indicate the importance of differential signaling of the MC4R. On the one hand, this is relevant for the therapy of patients with monogenic obesity. Additionally, this mechanism can also be used to identify patients with certain mutations in the MC4R who would benefit from drug therapy with an MC4R agonist. Moreover, a detailed knowledge of MC4R signaling enables the optimization of drug intervention strategies.
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