Abstract
Background: Melanocortin 4 receptor (MC4R), a notable component of the leptin-melanocortin system, regulates appetite, body weight, and energy homeostasis. MC4R is mediated by the melanocortins, a group of peptide hormones that include adrenocorticotropic hormone (ACTH), melanocyte-stimulating hormone (MSH), and Agouti-related peptide (AgRP). MC4R belongs to the group of G protein-coupled receptors (GPCRs). MC4R has been a promising target for the treatment of obesity for a long time. However, animal studies reported serious cardiovascular side effects with the many tested MC4R agonists. Therefore, despite the positive effects on body weight and food intake, these side effects delayed the development of a pharmacological therapeutic option. In November 2020, a new weight-control drug called Setmelanotide was approved by FDA for the treatment of severe genetic obesity in patients suffering from POMC deficiency or leptin receptor deficiency. Our aim from this study is to understand why MSH has cardiovascular side effects while Setmelanotide doesn’t. Our hypothesis is that Setmelanotide can activate MC4R via different signaling pathways than MSH. We are using several cell lines (HEK-MC4R, GT1-7 Hypothalamic cells and Human skeletal muscles). We are studying both G protein-dependent (cAMP) as well as G protein-independent (ERK1/2 phosphorylation and Insulin signaling) pathways. We detect distinct MC4R activation by Setmelanotide of the different signaling pathways in a tissue-dependent manner.
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