👤 Eleanor Raffan

The melanocortin-4 receptor (MC4R) is a G protein-coupled receptor with an essential role in appetite suppression and energy homeostasis. Genetic mutations in the receptor and components of its signalling pathway that cause obesity in humans, dogs and rodent models have revealed important insights into how the receptor signals and what regulates its cell surface expression. Structural studies have identified calcium as a critical cofactor for agonist binding and receptor function, while several transmembrane proteins have been shown to modulate MC4R activity. Here, we describe recent developments in our understanding of how accessory proteins and cofactors, identified using genomic approaches and screens for protein interaction, modify MC4R trafficking and signalling. We discuss how signalling by G Show less

Hypothalamic neurons expressing either POMC or AGRP sense nutritional state directly and indirectly and transmit these neuropeptide signals to other brain centres through the melanocortin 3 and 4 receptors. MC4R is primarily concerned with the control of appetite and energy expenditure while MC3R is more closely related to the control of linear growth and the timing of puberty. The role of MC3R in the long-term control of energy balance and body composition is less clear, particularly in humans. We have undertaken studies in humans, domestic dogs and mice with the goal of clarifying the relative impact of MC3R deficiency on energy balance, growth and sexual development. By studying three large consanguineously enriched cohorts, totalling approximately 300K people, we identified nine individuals who are homozygous for functionally null MC3R variants. The body mass index (BMI) of the homozygous MC3R variant carriers was not significantly different from that of age, sex and demographically matched controls, with six of the nine homozygotes having a BMI <30 kg/m Show less

Obesity is a heritable disease, but its genetic basis is incompletely understood. Canine population history facilitates trait mapping. We performed a canine genome-wide association study for body condition score-a measure of obesity-in 241 Labrador retrievers. Using a cross-species approach, we showed that canine obesity genes are also associated with rare and common forms of obesity in humans. The lead canine association was within the gene DENN domain containing 1B ( Show less