Pharmacological chaperone action in humanized mouse models of MC4R-linked obesity

JCI Insight. 2021 Feb 22;6(4):e132778. doi: 10.1172/jci.insight.132778.

Abstract

MC4R mutations represent the largest monogenic cause of obesity, resulting mainly from receptor misfolding and intracellular retention by the cellular quality control system. The present study aimed at determining whether pharmacological chaperones (PCs) that restore folding and plasma membrane trafficking by stabilizing near native protein conformation may represent valid therapeutic avenues for the treatment of melanocortin type 4 receptor-linked (MC4R-linked) obesity. To test the therapeutic PC potential, we engineered humanized MC4R (hMC4R) mouse models expressing either the WT human MC4R or a prevalent obesity-causing mutant (R165W). Administration of a PC able to rescue cell surface expression and functional activity of R165W-hMC4R in cells restored the anorexigenic response of the R165W-hMC4R obese mice to melanocortin agonist, providing a proof of principle for the therapeutic potential of MC4R-targeting PCs in vivo. Interestingly, the expression of the WT-hMC4R in mice revealed lower sensitivity of the human receptor to α-melanocyte-stimulating hormone (α-MSH) but not β-MSH or melanotan II, resulting in a lower penetrance obese phenotype in the WT-hMC4R versus R165W-hMC4R mice. In conclusion, we created 2 new obesity models, a hypomorphic highlighting species differences and an amorphic providing a preclinical model to test the therapeutic potential of PCs to treat MC4R-linked obesity.

Keywords: G protein–coupled receptors; Melanocortin; Metabolism; Obesity; Therapeutics.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Blood Glucose
  • Body Weight
  • Carrier Proteins / metabolism
  • Cell Membrane / metabolism
  • Disease Models, Animal
  • Female
  • HEK293 Cells
  • Humans
  • Male
  • Mice
  • Mutation
  • Obesity / metabolism*
  • Peptides, Cyclic
  • Phenotype
  • Protein Conformation
  • Receptor, Melanocortin, Type 4 / chemistry*
  • Receptor, Melanocortin, Type 4 / genetics*
  • Receptor, Melanocortin, Type 4 / metabolism*
  • alpha-MSH / analogs & derivatives
  • alpha-MSH / metabolism
  • alpha-MSH / pharmacology

Substances

  • Blood Glucose
  • Carrier Proteins
  • MC4R protein, human
  • MC4R protein, mouse
  • Peptides, Cyclic
  • Receptor, Melanocortin, Type 4
  • melanotan-II
  • alpha-MSH

Grants and funding

The work was supported by CIHR, Operating (MOP10501) and Foundation (FDN148431) grants to M.B. and Operating grant (MOP 119436) to D.R.. The work was also funded by a Pfizer/IRICoR partnership grant to M.B.