The melanocortin-4 receptor gene (MC4R) is involved in central energy homeostasis and body weight regulation. Both endogenous anorexigenic and orexigenic ligands bind to the receptor.¹ Under normal conditions, the anorexigenic tone prevails as revealed by the fact that Mc4r knock-out mice² develop elevated body weight. Mc4r^−/− mice show higher food intake but a similar metabolic rate and similar decreased physical activity compared to wild type (WT) mice of the same strain.^2–4 In comparison to a standard low fat diet, this deviant regulation of energy homeostasis is even more pronounced upon intake of a moderately fat diet,⁵ which leads to an even higher body mass.

In all studies, the effect on body weight is smaller in heterozygous than in homozygous knockout mice, but the exact degree of dominance is not clear. In heterozygous Mc4r^+/− animals, body mass is increased on average by about 7–45% and in homozygous Mc4r^−/− by 50–100% compared to WT^2–5 with substantial overlap between groups. The mutations might have a sex dependent effect, but the results are contradictory. In one study, the effect in males was only about half of that in females.² However, two studies did not detect a sex by genotype interaction in this Mc4r^−/− strain.^4,5 One study in a different knockout line of the same inbred strain found a sex by genotype interaction in the opposite direction, with only a marginal effect in heterozygous females whereas heterozygous males had a body weight intermediate between WT and homozygous knockouts.³

The first mutations in the human MC4R gene were reported in extremely obese probands.^6–8 Since then, several other studies investigated the association of different MC4R mutations with obesity. According to a recent overview,⁹ at least 34 putatively functionally relevant …