It is known that the loss of function
mutations of the melanocortin 4 receptor (MC4R) gene lead to severe
obesity in humans and in mice. These genetic mutations disrupt the
appetite control centers in the hypothalamus and lead to severe obesity.
In the March 20, 2003 issue of the New Eng J Med, two papers were
published which clarify the clinical syndrome resulting from the mutations
in the appetite controlling MC4R gene.In the first paper, Farooqi et al
determined the nucleotide sequence of the MC4R gene, which is known to be
a cause of a monogenic form of obesity. They studied 500 probands with
severe obesity. In these families they examined the cosegregation of
identified mutations, and in the subjects who were found to have MC4R
deficiency they performed a metabolic-endocrine evaluation and
characterized their clinical phenotype. The results were correlated with
the signaling properties of mutant receptors. Twenty-nine probands (5.8%)
had mutations in MC4R; 23 were heterozygous and 6 were homozygous.
Mutation carriers were severely obese; their mean percentage of body fat
was 43% of their body composition. Excess body weight gain was evident
since the first year of life. They also presented increased lean body
mass, increased linear growth, hyperphagia and severe hyperinsulinemia.
The serum leptin and lipid levels, the metabolic rate, and thyroid,
adrenal and reproduction function were normal. Homozygous individuals were
more severely affected than the heterozygous ones. The subjects with
mutations who retained some residual signaling capacity had a less severe
phenotype than those with a totally absent signaling capacity. MC4R
mutations resulted in a distinct obesity syndrome inherited in a
co-dominant manner. The authors concluded that MC4R alterations play a key
role in the development of a distinct form of severe obesity commencing in
early childhood.
In the second paper, Branson et al studied the interactions of genetic
and environmental factors which may have a bearing on the development of
obesity in MC4R affected individuals. Four hundred sixty-nine severely
obese white subjects with an average age of 42 years and with a mean
body-mass index of 44, and 25 control subjects with normal weight and no
history of obesity or dieting were included in this study. They sequenced
(1) the complete MC4R coding region, (2) the proopiomelanocortin gene
(POMC) region which encodes the
MSH. The
authors concluded that binge eating is a major phenotypic
characteristic of subjects with a mutation in MC4R, a candidate gene for
the control of eating behavior.
Farooqi IS et al. Clinical Spectrum of Obesity and Mutations in the
Melanocortin 4 Receptor Gene. New Eng J Med 2003;348:1085-1095.
Branson R et al. Binge Eating as a Major Phenotype of Melancortin 4
Receptor Gene Mutations. New Eng J Med 2003;348:1096-1103.
Editor’s Comment: These two papers simultaneously published in the
New Eng J Med are landmark studies. They contribute greatly to the
understanding of the pathogenesis of obesity in humans. Farooqi and
colleagues determined what proportion of obesity is attributed to a
mutated gene of MC4R. They found that about 6% of severely obese
individuals who had obesity since early childhood had these mutations.
Thus, patients carrying MC4R mutations constituted an important subgroup
of the severely overweight population. Given the high prevalence of
observed MC4R deficiency, it appears that this condition represents the
most common form of monogenic obesity in humans. Pediatricians and
pediatric endocrinologists should be on the look out for this, especially
in children who gain excess weight beginning in early childhood.
Clinically, these patients differ from those with Prader Willi syndrome,
who also have another form of monogenic severe obesity, by the normal
stature and muscle development which are abnormal in Prader Willi
syndrome.
The second study showed that overweight people who are binge eaters are
more likely to harbor genetic mutations of MC4R than overweight people who
constantly overeat. Until now, binge eating was considered a psychological
phenomenon or disorder. For the first time a genetically driven
characteristic was demonstrated. MC4R mutations appeared to disrupt brain
signals governing satiety.
Both studies clearly document that there are severely obese individuals
who overeat, not because of lack of will power, but because they have a
genetically determined pathological syndrome.
However, these data also demonstrate that there are some individuals
who have genetically determined mutations, yet are not obese. The reverse
also occurs; specifically, binge eating behavior may occur and not be
found to be associated with genetic mutations of MC4R. Thus, these two
reports also support the thesis that the etiology of obesity is
multifactorial, even in individuals who have a genetically determined
alteration in the appetite control centers in the hypothalamus. In these
patients, as well as in other obesities, excess energy intake over energy
expenditures must occur for obesity to develop.
The reader is encouraged to review these two papers in detail, as well
as to study the accompanying editorial by List and Habener1 who
clearly described the model of the homeostatic circuit regulating energy
balance via the MC4 receptor. These authors point out that several
hormones are known to influence the appetite control centers in the
hypothalamus (Figure). MC4R deficiency is
clearly implicated in the etiopathogenic mechanisms in some cases of
severe obesity and binge eating, through short-circuiting the regulation
of appetite in the hypothalamus. MC4R deficiency decreases the signals of
anorixegenic pathways, such as CRH and TRH; and prevents the inhibition of
orixegenic pathways, such as MSH and orexin. The result is increased food
intake. The melanocortin agonist a MSH is a peptide that is produced by
the POMC, and is an agonist of MC4R. On the other hand, leptin reduces
food intake through stimulation of the expression of POMC and the
production of MSH, while inhibiting MC4R antagonists such as the
agouti-related protein.
The abnormal molecular physiology demonstrated in MC4R deficient
patients constitutes an important discovery of a missing link between
genes and behavior. However, there is a lot more to be uncovered before we
fully understand satiety in individuals with MC4R gene mutations, as well
as in other obesity syndromes, and in normal individuals.2
Fima Lifshitz, MD
References
1.
List JF, Habener JF. New
Eng J Med 2003;348:1160-1163.
2.
Gotoda T. New Eng J Med
2003;349:606-609.
