title: Defect in MAPK signaling as a cause for monogenic obesity caused by inactivating mutations in the melanocortin-4 receptor gene.
abstract: The melanocortin-4 receptor (MC4R) is a Family A G protein-coupled receptor that plays an essential role in regulating energy homeostasis, including both energy intake and expenditure. Mutations leading to a reduced MC4R function confer a major gene effect for obesity. More than 170 distinct mutations have been identified in humans. In addition to the conventional Gs-stimulated cAMP pathway, the MC4R also activates MAPKs, especially ERK1/2. We also showed there is biased signaling in the two signaling pathways, with inverse agonists in the Gs-cAMP pathway acting as agonists for the ERK1/2 pathway. In the current study, we sought to determine whether defects in basal or agonist-induced ERK1/2 activation in MC4R mutants might potentially contribute to obesity pathogenesis in patients carrying these mutations. The constitutive and ligand-stimulated ERK1/2 activation were measured in wild type and 73 naturally occurring MC4R mutations. We showed that nineteen mutants had significantly decreased basal pERK1/2 level, and five Class V variants (where no functional defects have been identified previously), C40R, V50M, T112M, A154D and S295P, had impaired ligand-stimulated ERK1/2 activation. Our studies demonstrated for the first time that decreased basal or ligand-stimulated ERK1/2 signaling might contribute to obesity pathogenesis caused by mutations in the MC4R gene. We also observed biased signaling in 25 naturally occurring mutations in the Gs-cAMP and ERK1/2 pathways.
authors.affiliation: 1. Department of Anatomy, Physiology, and Pharmacology, College of Veterinary Medicine, Auburn University, Auburn, Alabama 36849-5519, USA. ; 2. Key Laboratory of Freshwater Animal Breeding, Ministry of Agriculture, College of Fisheries, Huazhong Agricultural University, Hubei Collaborative Innovation Center for Freshwater Aquaculture, Wuhan, Hubei 430070, China.
authors.forename: Shan
authors.initials: S
authors.lastname: He
authors.affiliation: 1. Department of Anatomy, Physiology, and Pharmacology, College of Veterinary Medicine, Auburn University, Auburn, Alabama 36849-5519, USA.
authors.forename: Ya-Xiong
authors.initials: YX
authors.lastname: Tao
mesh_terms: D057809:HEK293 Cells; D006801:Humans; D007091:Image Processing, Computer-Assisted; D015151:Immunoblotting; D008163:Luminescent Measurements; D020935:MAP Kinase Signaling System / Q000502:physiology*; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism*; D008958:Models, Molecular; D009154:Mutation / Q000235:genetics; D009765:Obesity / Q000235:genetics*; D010766:Phosphorylation; D044105:Receptor, Melanocortin, Type 4 / Q000235:genetics*
chemical_list: D044105:Receptor, Melanocortin, Type 4; D020929:Mitogen-Activated Protein Kinase Kinases
keywords: Melanocortin-4 receptor; biased signaling.; extracellular signal-regulated kinases 1 and 2 signaling; naturally occurring mutation