As expected for a loss-of-function mutation resulting from receptor misfolding, mice harboring 2 copies of the R165W-hMC4R allele did not respond any more to central or peripheral administration of MTII melanocortin agonist, consistent with the notion that the lack of receptor expression at the cell surface is the primary cause leading to obesity. This evidence concerns the gene MT2A and obesity due to melanocortin 4 receptor deficiency.