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Melanocortin-4 Receptor

Melanocortin-4 Receptor. The Obesity Gene. Melanocortin-4 Receptor. Chromosome 18q22 Centrally expressed G protein-coupled receptor 1-6% early onset or severe adult obesity Signals by: Interaction with Gs Activation of adenylate cyclase. Obese Phenotype. Haploinsufficiency

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Melanocortin-4 Receptor

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  1. Melanocortin-4 Receptor The Obesity Gene

  2. Melanocortin-4 Receptor • Chromosome 18q22 • Centrally expressed G protein-coupled receptor • 1-6% early onset or severe adult obesity • Signals by: • Interaction with Gs • Activation of adenylate cyclase

  3. Obese Phenotype • Haploinsufficiency • Mechanisms controlling the number of MC4Rs available for hormone binding • Signal transduction • Mutation of prohormone convertases which process POMC

  4. Receptor control • Anorexigenic agonist α-mealnocyte stimulating hormone (α-MSH) • Orexigenic antagonist agouti-related protein (AGRP)

  5. α-MSH • Pro-opiomelanocortin (POMC) derived peptide ligand • 13 amino acids • Maintained by leptin • Activates MCR-1,3,4, and 5

  6. α-MSH activation of MC4R • Occurs in the paraventricular nucleus of the hypothalamus • Receptor couples to heterotrimeric Gs protein • Activates adenylyl cyclase • Prevents hyperphagia and obesity

  7. AGRP • 46 amino acids • C-terminal cysteine-rich motif • Inhibits MCR-3, 4, & 5 • Competitive antagonist • Inverse agonist

  8. Hunger Low energy balance Decrease leptin levels Stimulate AGRP Decrease POMC Decrease α-MSH Hunger Repress MC4R

  9. Identified Point Mutations • In MC4R: • Transmembrane segments • Extracellular and intracellular loops

  10. Genetic Mutations • Arginine to glutamine subsitution • Alanine subsitutions • N-terminal mutations

  11. R165Q • Mutation on codon 165 • Highest frequency • Poorly expressed on the cell surface • Reduces MC4R binding activity by 70%

  12. Alanine Substitutions • Observed at E100, D122, and D126 -key acidic residues -necessary for repression or activation • Ended α-MSH activation • Changes constitutive activity of receptor

  13. N-terminal • Domain functions as intramolecular ligand • Maintains anorexigenic catabolic state • R18C, R18H, & R18L -only MC4R amino acid detected with 3 obesity related mutations • Competition of AGRP and α-MSH same within wild type and mutant receptors • Results in loss of constitutive activity

  14. Risk Factors of Obesity • Cardiovascular disease • Hypertension • Type II diabetes • Certain cancers

  15. Summing it up • 8% of the worlds adult population is clinically obese • In the last 20 years, the United States obesity rate has increased from 15% to 25% • MC4R mutations only responsible for 1-6% of the severely obese

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