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.
Highlights
Severe obesity is generally considered a multifactorial disease caused by both genetic and environmental factors resulting in an energy imbalance
We used homologous recombination in embryonic stem (ES) cells to replace the mouse mc4r coding gene by either the human WT melanocortin type 4 receptor (MC4R) tagged at the N-terminus with a c-myc epitope or a mutant form of the human MC4R carrying an obesity-linked mutation at position R165→W in the humanized MC4R (hMC4R) coding sequence tagged at the N-terminus with 3 tandem sequences of the HA epitope
This study describes 2 potentially unique humanized MC4R-transgenic mouse models harboring either a WT or a mutant human allele in place of the mouse receptor allele
Summary
Severe obesity is generally considered a multifactorial disease caused by both genetic and environmental factors resulting in an energy imbalance. The predisposition to obesity is largely polygenic but can be monogenic [1, 2]. Mutations occurring in the melanocortin type 4 receptor (MC4R), a key component of the central regulation of energy homeostasis, have been associated with severe familial obesity and reported as the most common monogenic cause of childhood obesity [3,4,5,6]. The prevalence of MC4R mutations in obese people varies substantially in frequency (1%–6% of the obese patients) depending on the ethnic origin, the severity of obesity, and the age of obesity onset of the population considered [7]. The mode of inheritance is defined as autosomal codominant with modulation of expression and of phenotype penetrance [6]
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