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Melanocortin 4 receptors and obesity

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Since all obesity results from an excess of energy intake over energy expenditure it follows that too much food and too little exercise must underlie the current obesity pandemic. It is tempting to blame fast food, cars, and television, and no doubt they share a lot of the blame, but could some people affected by modern lifestyle changes be genetically predisposed to succumb? Or have the genetic syndromes always existed and are they irrelevant to the recent increase?

Leptin is produced by adipocytes and stimulates production of proopiomelanocortin in the arcuate nucleus of the hypothalamus. Proopiomelanocortin is degraded by prohormone convertases to α melanocyte-stimulating hormone that acts via hypothalamic melanocortin 4 receptors (MC4Rs) to reduce appetite. It has been estimated that gene mutations in this system could account for between 0.5% and 4% of cases of obesity, but researchers in Cambridge (

; see also

) have found MC4R gene mutations in almost 6% of 500 people with severe obesity (mean standard deviation score for body mass index 4.2) beginning before the age of 10 years.

Nucleotide sequencing of the MC4R gene in the 500 unrelated probands showed mutations in 29, 23 heterozygotes and six homozygotes. These mutations were absent from 100 alleles of non-obese people. Family studies showed codominant inheritance. All relatives of heterozygous probands who had the mutation also had early onset obesity. Among the families of homozygous probands all 12 homozygotes, but only 17 of 25 heterozygotes, had early onset obesity. Homozygotes in these families were more obese than heterozygotes. The phenotype included severe early onset obesity, increased lean mass (greater than in leptin deficiency), increased growth in height, hyperphagia, severe hyperinsulinaemia, and increased bone density. Hyperinsulinaemia and hyperphagia tended to decrease in late childhood and early adult life. Analysis of gene function in cell cultures showed that residual function was associated with less severe phenotype.

In another paper in the same issue of the

) researchers in Switzerland and Germany report binge eating in all of 20 subjects with severe obesity and an MC4R mutation, but in only 17 of 120 similarly obese subjects without an MC4R mutation. Leptin receptor mutations were not associated with binge eating.

Genetic causes of obesity are being delineated increasingly. What contribution, if any, this knowledge has made to understanding the worldwide increase in obesity seems uncertain. The hope, though, must be that it may lead to new approaches to treatment.