Human MC4R variants affect endocytosis, trafficking and dimerization revealing multiple cellular mechanisms involved in weight regulation

The Melanocortin-4 Receptor (MC4R) plays a pivotal role in energy homeostasis. We used human MC4R mutations associated with an increased or decreased risk of obesity to dissect mechanisms that regulate MC4R function. Most obesity-associated mutations impair trafficking to the plasma membrane (PM), whereas obesity-protecting mutations either accelerate recycling to the PM or decrease internalization, resulting in enhanced signaling. MC4R mutations that do not affect canonical Gαs protein-mediated signaling, previously considered to be non-pathogenic, nonetheless disrupt agonist-induced internalization, β-arrestin recruitment, and/or coupling to Gαs, establishing their causal role in severe obesity. Structural mapping reveals ligand-accessible sites by which MC4R couples to effectors and residues involved in the homodimerization of MC4R, which is disrupted by multiple obesity-associated mutations. Human genetic studies reveal that endocytosis, intracellular trafficking, and homodimerization regulate MC4R function to a level that is physiologically relevant, supporting the development of chaperones, agonists, and allosteric modulators of MC4R for weight loss therapy. [Display omitted] •Obesity-associated MC4R mutations that do not reduce cAMP disrupt other processes•MC4R mutations impact receptor homodimerization, endocytosis, and trafficking•Obesity-protecting mutations increase plasma membrane MC4Rs and enhance signaling•Multiple mechanisms regulate melanocortin tone to a physiologically relevant level Using mutations in the human Melanocortin-4 Receptor (MC4R), Brouwers et al. identify receptor trafficking and endocytosis, coupling to Gαs/β-arrestins, and homodimerization as mechanisms involved in the regulation of body weight that may be targeted for weight loss therapy.