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 25 May 2018

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News

Binge eating and obesity due to melanocortin 4 receptor gene mutations

Two separate teams of researchers in this week's New England Journal of Medicine investigate the influence of melanocortin 4 receptor gene mutations on binge eating and obesity.

News image

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Melanocortin 4 receptor (MC4R) deficiency is the commonest monogenic form of obesity. However, the clinical spectrum and mode of inheritance have not been defined.

In addition, pathophysiological mechanisms leading to obesity are poorly understood, and there is little information regarding genotype-phenotype correlations.

In this study, researchers from Cambridge, England, determined the nucleotide sequence of the MC4R gene in 500 probands with severe childhood obesity.

All mutation carriers reported binge eating.
New England Journal of Medicine

The research team also undertook family studies to examine cosegregation of identified mutations with obesity.

Subjects with MC4R deficiency underwent metabolic and endocrine evaluation. The team then correlated these results with the signaling properties of mutant receptors.

The researchers found that 6% of probands had mutations in MC4R. Of these, 23 were heterozygous and 6 were homozygous.

The team determined that mutation carriers had severe obesity, increased lean mass, increased linear growth, hyperphagia, and severe hyperinsulinemia. However, homozygotes were more severely affected than heterozygotes.

In addition, they found that subjects with mutations retaining residual signaling capacity had a less severe phenotype.

Dr Sadaf Farooqi's team concluded, "Mutations in MC4R result in a distinct obesity syndrome that is inherited in a codominant manner".

"Mutations leading to complete loss of function are associated with a more severe phenotype."

"The correlation between the signaling properties of these mutant receptors and energy intake emphasizes the key role of this receptor in the control of eating behavior in humans."

In a separate but related article in the same publication, researchers looked at, "Binge eating as a major phenotype of melanocortin 4 receptor gene mutations".

In this study, a team of researchers assessed 469 severely obese white subjects (370 women and 99 men, mean age 41 years, BMI 44.1).

They sequenced the complete MC4R coding region, the region of the proopiomelanocortin gene (POMC) encoding the melanocyte-stimulating hormone, and the leptin-binding domain of LEPR.

In addition, 15 women and 10 men without a history of dieting or a family history of obesity served as normal-weight controls (mean age 47.7 years, BMI 21.6).

The team also collected detailed phenotypic data. This included information on body fat, resting energy expenditure, diet-induced thermogenesis, serum concentrations of leptin, and eating behavior.

The researchers found that 5% of the obese subjects and 4% of the control subjects had MC4R mutations, including 5 novel variants.

They then matched 20 of the 24 obese subjects with an MC4R mutation with 120 of the 445 obese subjects without an MC4R mutation.

The research team found that all mutation carriers reported binge eating. This compared with 14% of obese subjects without mutations, and 0% of the normal-weight subjects without mutations.

The team also determined that the prevalence of binge eating was similar among carriers of mutations in the leptin-binding domain of LEPR and noncarriers.

No mutations were found in the region of POMC encoding melanocyte-stimulating hormone.

Dr Ruth Branson's team, "Binge eating is a major phenotypic characteristic of subjects with a mutation in MC4R, a candidate gene for the control of eating behavior".

New Engl J Med 2003; 348: 1085-95, 1096-103
21 March 2003

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