Obesity is generally a polygenic condition, arising from the effects of a variety of genetic factors (mostly unidentified, so far) interacting with the environment. In recent years, however, some largely monogenic forms of obesity have been identified that are associated with mutations in genes that encode components of biochemical pathways involved in the control of appetite and eating behaviour. The melanocortin 4 receptor (MC4R) protein is one of these components, and mutations in the MC4R gene have been found by some research groups in about 4-5% of severely obese people. Two recent papers in the New England Journal of Medicine provide further insight into the relationship between MC4R mutations and obesity. Farooqi et al report that 5.8% of 500 unrelated people with severe, childhood-onset obesity had mutations in the MC4R gene that were not found in unaffected control subjects [Farooqi, IS et al (2003) N Engl J Med 348, 1085-1095]. Functional analysis confirmed that the mutant receptor proteins were inactive or only partially active. Relatives of mutation carriers were genotyped in order to study the segregation of mutant alleles with obesity. In some families, obesity was very strongly associated with the presence of a single MC4R mutation, whereas in other families ascertained through a homozygous proband (all of whom were of Indo-European origin), homozygotes were more severely affected than heterozygotes. The authors suggest that the penetrance of MC4R mutations may vary in different ethnic groups. As well as increased body fat, MC4R mutation carriers had increased lean body mass, higher blood insulin levels and showed over-eating behaviour; the severity of these characteristics could be correlated with the severity of the effect of the MC4R mutation(s) on receptor activity.
Branson et al compared the sequence of several genes involved in appetite control and eating behaviour between 25 normal controls and 469 severely obese, white subjects [Branson, R et al (2003) N Engl J Med 348, 1096-1103]. 24 of the obese people (5.1%) had MC4R mutations, although so did one control. (4%). Interestingly, when obese mutation carriers were compared with obese non-carriers, all the mutation carriers but only 14% of the non-carriers were found to show binge-eating behaviour [but see the accompanying editorial by List, JF et al (2003; N Engl J Med 348, 1160-1163) for a note of caution about these results]. Neither Branson et al, nor Farooqi et al, found an effect of MC4R mutations on metabolic rate.
Comment: In obesity research, as in other areas, studies on people with extreme phenotypes have led to the identification of a small number of genes that, when mutated, confer a high risk for the condition. At most 5% of obese people have mutations in MC4R, however, indicating that there must be other predisposing genes, most of which are likely, individually, to have much smaller effects. Nevertheless, research on families affected by highly-penetrant mutations in genes such as MC4R may lead to the development of effective therapies for these families, and may also yield important information about the biological control of appetite and eating behaviour in general.