Obese melanocortin-4-receptor-deficient (MC4R-/-) male mice are reported to have erectile dysfunction, while homozygous MC4R-/- female mice are apparently fertile. A recently established obese mouse strain, carrying an inactivating mutation in the MC4R gene, revealed difficulties in breeding for the homozygous female mice. This prompted us to determine the presence of follicles and corpora lute...

The molecular basis of ligand recognition by the melanocortin 4 receptor (MC4R) has not been fully defined. In this study, we investigated the molecular determinants of MC4R ligand binding, employing a large array of ligands, using three approaches. First, molecular modeling of the receptor was used to identify Phe284, in transmembrane (TM) 7, as a potential site of ligand interaction. Mutation...

Mutations in the melanocortin-4 receptor (MC4R) gene are the most frequent monogenic causes of severe obesity. Most mutations have been described as heterozygous with loss of function, suggesting that haploinsufficiency is the most likely mechanism of dominant inheritance. We detected a heterozygous mutation, D90N, in a patient with severe early-onset obesity. Functional characterization of the...

We assessed the efficacy of simultaneous agonism at the glucagon-like peptide-1 receptor (GLP-1R) and the melanocortin-4 receptor (MC4R) for the treatment of obesity and diabetes in rodents. Diet-induced obese (DIO) mice were chronically treated with either the long-acting GLP-1R agonist liraglutide, the MC4R agonist RM-493 or a combination of RM-493 and liraglutide. Co-treatment of DIO mice wi...

Mice with homozygous genetic disruption of the melanocortin-4 receptor gene (MC4R-/-) are known to be hyperphagic and become obese, while those with disruption of the melanocortin-3 receptor gene (MC3R-/-) do not become markedly obese. The contribution of MC3R signaling in energy homeostasis remains little studied. In the present work, we compare MC3R-/- mice with wild-type (WT), MC4R-/-, and m...

The Melanocortin Receptor Accessory Protein 2 (MRAP2) is an important regulator of energy homeostasis and its loss causes severe obesity in rodents. MRAP2 mediates its action in part through the potentiation of the MC4R, however, it is clear that MRAP2 is expressed in tissues that do not express MC4R, and that the deletion of MRAP2 does not recapitulate the phenotype of Mc4r KO mice. Consequent...

Bariatric surgery is the most effective long term weight-loss therapy for severe and morbidly obese patients. Melanocortin-4 Receptor (MC4R) mutations, the most frequent known cause of monogenic obesity, affect the regulation of energy homeostasis. The impact of such mutations on weight loss after bariatric surgery is still debated.The objective is to determine the impact of MC4R status on weig...

BACKGROUND Neuropathic pain is characterised by spontaneous ongoing or shooting pain and evoked amplified pain responses after noxious or non-noxious stimuli. Neuropathic pain develops as a result of lesions or disease affecting the somatosensory nervous system either in the periphery or centrally. Melanocortin 4 receptor (MC4R) plays an important role in the initiation of neuropathic pain but ...

Melanocortin-4 receptor (Mc4r)-expressing neurons in the autonomic nervous system, particularly in the paraventricular nucleus of the hypothalamus (PVH), play an essential role in blood pressure (BP) control. Mc4r-deficient (Mc4rKO) mice are severely obese but lack obesity-related hypertension; they also show a reduced pressor response to salt loading. We have previously reported that lean juve...

Bioactive peptides derived from the prohormone, pro-opiomelanocortin (POMC), are generated in neurons of the hypothalamus and act as endogenous ligands for the melanocortin-4 receptor (MC4R), a key molecule underlying appetite control and energy homeostasis. It is therefore important to understand many aspects of POMC gene regulation in the brain, as pharmacological manipulation of POMC express...