• G protein-coupled receptors
• MRAP2 variants
• Obesity
• Signal Transduction

• Humans
• Receptor, Melanocortin, Type 4/genetics
• Receptor, Melanocortin, Type 4/metabolism
• Obesity/genetics
• Obesity/metabolism
• Signal Transduction/genetics
• HEK293 Cells
• Mutation
• Cyclic AMP/metabolism
• Adaptor Proteins, Signal Transducing/genetics
• Adaptor Proteins, Signal Transducing/metabolism

• An Academy of Medical Sciences Springboard Award
• Global Challenges Research Fund
• SBF004|1034 Government Department of Business, Energy and Industrial Strategy and the Wellcome Trust
• British Heart Foundation

• G protein-coupled receptor
• adaptation
• evolution
• selection
• signal transduction

• Animals
• Receptors, G-Protein-Coupled/genetics
• Receptors, G-Protein-Coupled/metabolism
• Humans
• Vertebrates/physiology
• Vertebrates/genetics
• Genomics
• Adaptation, Physiological/genetics

• 421152132 Deutsche Forschungsgemeinschaft (DFG)
• 209933838 Deutsche Forschungsgemeinschaft (DFG)

• Cyclic AMP
• Downstream
• G protein
• Leptin-melanocortin pathway
• Mutation
• Obesity syndromes
• Screening
• Setmelanotide

• Energy homeostasis
• Fish (Teleost)
• GPCRs
• Melanocortin receptors
• Neuropeptide Y receptors

The melanocortinergic pathway orchestrates the energy homeostasis and impairments in this system often lead to an increase in body weight. Rare variants in the melanocortin 4 receptor (MC4R) gene resulting in partial or complete loss of function have been described with autosomal co-dominant inheritance. These mutations are the most common cause of non-syndromic monogenic obesity. In this context, this study aimed to sequence the MC4R gene in a Brazilian cohort of adults with severe obesity.

This study included 163 unrelated probands with Body Mass Index (BMI) ≥ 35 kg/m², stratified into three groups, according to the period of obesity onset. From the total sample, 25 patients were enrolled in the childhood-onset group (0–11 years), 19 patients in the adolescence/youth-onset group (12–21 years), and 119 patients in the adult-onset group (>21 years). Blood pressure, anthropometric and biochemical characteristics were obtained, and the MC4R coding region of each subject’s DNA was assessed using automated Sanger sequencing.

Significant anthropometric differences between the groups were observed. Higher body weight and BMI medians were found in patients with childhood-onset or adolescence/youth-onset when compared to the adulthood-onset obesity group. A total of five mutations were identified, including four missense variants: p.Ser36Thr, p.Val103Ile, p.Ala175Thr, and p.Ile251Leu. Additionally, we observed one synonymous variant (p.Ile198=). The p.Ala175Thr variant was identified in a female case with severe obesity and adulthood-onset. This variant was previously described as a partial loss-of-function mutation, in which the minor allele poses dominant-negative effect, probably resulting in reduced cAMP activity.

This study showed a prevalence of common and rare variants in a cohort of Brazilian adults with severe obesity and candidates to bariatric surgery. We have identified a rare potentially pathogenic MC4R variant in a Brazilian patient with severe and adulthood-onset obesity.

• MC4R
• adulthood-onset obesity
• mutation
• non-syndromic monogenic obesity
• severe obesity

To determine the prevalence of Melanocortin-4 Receptor (MC4R) mutations in a cohort of children and adolescents with overweight or obesity and to determine whether treatment responses differed between carriers and noncarriers.

Using target region capture sequencing, an MC4R mutation screen was performed in 1261 Danish children and adolescents enrolled at a tertiary multidisciplinary childhood obesity treatment center. Measurements of anthropometrics, blood pressure, fasting blood biochemistry including lipid and hormone levels, and dual-energy X-ray absorptiometry were performed at baseline and throughout treatment.

Of 1209 children and adolescents that met all criteria to be included in the described analyses, 30 (2.5%) carried damaging or unresolved MC4R mutations. At baseline, mutation carriers exhibited higher concentrations of plasma thyroid-stimulating hormone (p = 0.003), and lower concentrations of plasma thyroxine (p = 0.010) compared to noncarriers. After a median of 1 year of treatment (range 0.5–4.0 years), body mass index (BMI) standard deviation score (SDS) was reduced in noncarriers but not in carriers, and this difference in treatment response was statistically significant (p = 0.005). Furthermore, HDL cholesterol was reduced in carriers, a response significantly different from that of noncarriers (p = 0.017).

Among Danish children and adolescents with overweight or obesity entering a tertiary lifestyle intervention, 2.5% carried damaging or unresolved MC4R mutations. In contrast to noncarriers, carriers of damaging or unresolved MC4R mutations failed to reduce their BMI SDS during obesity treatment, indicating a need for personalized treatment based on the MC4R genotype.

The melanocortin 4 receptor (MC4R) is a key player in hypothalamic weight regulation and energy expenditure as part of the leptin–melanocortin pathway. Mutations in this G protein coupled receptor (GPCR) are the most common cause for monogenetic obesity, which appears to be mediated by changes in the anorectic action of MC4R via G_S-dependent cyclic adenosine-monophosphate (cAMP) signaling as well as other signaling pathways. To study potential bias in the effects of MC4R mutations between the different signaling pathways, we investigated three major MC4R mutations: a G_S loss-of-function (S127L) and a G_S gain-of-function mutant (H158R), as well as the most common European single nucleotide polymorphism (V103I). We tested signaling of all four major G protein families plus extracellular regulated kinase (ERK) phosphorylation and β-arrestin2 recruitment, using the two endogenous agonists, α- and β-melanocyte stimulating hormone (MSH), along with a synthetic peptide agonist (NDP-α-MSH). The S127L mutation led to a full loss-of-function in all investigated pathways, whereas V103I and H158R were clearly biased towards the G_q/11 pathway when challenged with the endogenous ligands. These results show that MC4R mutations can cause vastly different changes in the various MC4R signaling pathways and highlight the importance of a comprehensive characterization of receptor mutations.

• G protein coupled receptor (GPCR)
• Melanocortin 4 receptor (MC4R)
• Melanocyte stimulating hormones MSH
• biased signaling

• Denisova
• GPCR
• Missense variants
• Neanderthal
• Peptides

• Animals
• Diabetic Nephropathies/genetics
• Diabetic Nephropathies/pathology
• Evolution, Molecular
• Genome, Human/genetics
• Haplotypes/genetics
• Hominidae/genetics
• Humans
• Neanderthals/genetics
• Obesity/genetics
• Obesity/pathology
• Peptides/genetics
• Platelet Aggregation/genetics
• Receptors, G-Protein-Coupled/genetics
• Risk Factors

• Adolescent
• Black or African American/genetics
• Age of Onset
• Child
• Child, Preschool
• Female
• Hispanic or Latino/genetics
• Humans
• Infant
• Male
• Mutation
• Pediatric Obesity/genetics
• Receptor, Melanocortin, Type 4/genetics
• Receptor, Melanocortin, Type 4/metabolism
• Severity of Illness Index

• UM1 HG006504 NHGRI NIH HHS
• U54 HG006542 NHGRI NIH HHS
• K12 DK094723 NIDDK NIH HHS
• R01 DK075787 NIDDK NIH HHS
• K23 DK110539 NIDDK NIH HHS
• R01 DK052431 NIDDK NIH HHS
• P30 DK026687 NIDDK NIH HHS
• UL1 TR000040 NCATS NIH HHS

• Gene pleiotropy
• lazy-thrifty genotype
• obesity
• peppy-thrifty genotype

• ethnic diversity
• genetic susceptibility
• obesity

Cetaceans, a group of mammals adapted to the aquatic environment that descended from terrestrial artiodactyls, exhibit tremendous interspecific differences in a number of phenotypes, including feeding behavior, such as filter feeding in the Mysticeti vs prey-hunting Odontoceti, and size, with the smallest cetacean, the vaquita, at 1.4 meters and the largest, the blue whale, reaching 33 meters. The Melanocortin-4 receptor (MC4R) regulates food intake, energy balance, and somatic growth in both mammals and teleosts. In this study, we examined allelic variants of the MC4R in cetaceans. We sequenced the MC4R from 20 cetaceans, and pharmacologically characterized 17 of these protein products. Results identified a single variation at amino acid 156 in the MC4R from representative species of major cetacean lineages uniquely associated with the toothed whales or Odontoceti (arginine at 156) and baleen whales or Mysticeti (glutamine at 156). The Q156 receptor variant found in the larger baleen whales was functionally less responsive to its endogenous anorexigenic ligand, α-MSH. Furthermore, the R156 receptor variant showed greater constitutive activity and a higher affinity for ligand. These data suggest that the MC4R may be one gene involved in the evolution of feeding ecology, energy balance, and body size in cetaceans.

• Genotype–phenotype correlation
• South Africa
• melanocortin 4 receptor
• obesity

• Animals
• Body Weight
• Breeding
• DNA/isolation & purification
• Female
• Gene Expression Profiling/methods
• Gene Expression Regulation
• Gene Frequency
• Genotype
• Italy
• Male
• Meat
• Muscle, Skeletal
• Phenotype
• Polymorphism, Single Nucleotide
• RNA, Messenger/genetics
• RNA, Messenger/metabolism
• Receptor, Melanocortin, Type 4/genetics
• Receptor, Melanocortin, Type 4/metabolism
• Swine/genetics

Candidate gene and genome-wide association studies have led to the discovery of nine loci involved in Mendelian forms of obesity and 58 loci contributing to polygenic obesity. These loci explain a small fraction of the heritability for obesity and many genes remain to be discovered. However, efforts in obesity gene identification greatly modified our understanding of this disorder. In this review, we propose an overlook of major lessons learned from 15 years of research in the field of genetics and obesity. We comment on the existence of the genetic continuum between monogenic and polygenic forms of obesity that pinpoints the role of genes involved in the central regulation of food intake and genetic predisposition to obesity. We explain how the identification of novel obesity predisposing genes has clarified unsuspected biological pathways involved in the control of energy balance that have helped to understand past human history and to explore causality in epidemiology. We provide evidence that obesity predisposing genes interact with the environment and influence the response to treatment relevant to disease prediction.

• Biologic pathways
• Mendelian randomization
• disease prediction
• food intake
• gene x environment interactions
• genetic continuum
• obesity
• positive selection.

• Adolescent
• Child
• Female
• Gene Frequency
• Heterozygote
• Humans
• Male
• Mutation
• Netherlands
• Obesity, Morbid/genetics
• Promoter Regions, Genetic
• Receptor, Melanocortin, Type 4/genetics

• Amino Acid Sequence
• Animals
• Base Sequence
• Body Weight/genetics
• Cattle/genetics
• Cloning, Molecular
• Cluster Analysis
• DNA Primers/genetics
• Evolution, Molecular
• Genetic Variation
• Haplotypes/genetics
• Molecular Sequence Data
• Mutation/genetics
• Open Reading Frames/genetics
• Phylogeny
• Receptor, Melanocortin, Type 4/genetics
• Sequence Analysis, DNA