US scientists have identified a rare genetic mutation that can directly cause obesity in some people.
The study by Boston Children's Hospital in US involved genetic surveys of several groups of obese humans and experiments in mice.
Mice with the genetic mutation gained weight even while eating the same amount of food as their normal counterparts; the affected gene, Mrap2, has a human counterpart (MRAP2) and appears to be involved in regulating metabolism and food consumption.
"These mice aren't burning the fat, they're somehow holding onto it. Mice with the genetic mutation gained more weight, and we found similar mutations in a cohort of obese humans," said the study's lead investigator Joseph Majzoub, chief of endocrinology at Boston Children's.
The protein created by the Mrap2 gene appears to facilitate signalling to a receptor in the brain called Mc4r, which helps increase metabolism and decrease appetite as part of a larger signalling chain involved in energy regulation.
Fat cells produce the hormone leptin, prompting receptors in the brain to instigate production of a second hormone, alpha-MSH. Mc4r detects this hormone with the aid of Mrap2, leading to a decrease in appetite and weight.
Mutations in this signalling chain, including mutations in Mc4r, are known to increase the likelihood of obesity.
Majzoub, first author Masato Asai, now at Nagoya University in Japan, and colleagues studied mice with the Mrap2 gene knocked out both overall and just in the brain. In both cases, the mice grew to about twice their normal size.
Weight gain was greatest when both copies of Mrap2 were knocked out, but the mice still showed weight gain and appetite increase with one working copy of the gene. The weight gain was more pronounced in males than females.
In addition, the mice without Mrap2 had more exaggerated weight gain when fed a high-fat diet than normal mice.
Surprisingly, while the mice without Mrap2 didn't eat more at first, they still gained weight faster than the controls. Later, their appetites increased and they continued to gain more weight than the controls, even when held to the same diet and quantity of food.
To investigate the gene in humans, Majzoub collaborated with Sadaf Farooqi, of the University of Cambridge, and others to investigate groups of obese patients from around the world.
The team found four mutations in the human equivalent of Mrap2 among the 500 people, all in patients with severe, early-onset obesity; each of the four affected patients had only one copy of the mutation.
While the finding suggests that these rare mutations directly cause obesity in less than 1 per cent of the obese population, the researchers suspect that other mutations in the gene might occur more commonly and might interact with other mutations and environmental factors to cause more common forms of obesity.
