It has long been established that an unbalanced diet, high in fats and excess sugars, can lead to poor health and obesity. Many people around the globe have difficulty measuring out appropriate portions of food and tend to over eat. The World Health Organization even said that obesity is an epidemic, starting in 2008. But, what if this worldwide weight gain was genetically based?

In a new study, researchers at Boston Children's Hospital identified a genetic cause of severe obesity, raising new questions on weight gain and energy use in the general obese population. Obesity occurs when a person eats too many fats and sugars that the body cannot hope to use all at once. The energy from these foods gets stored as fat all over the body, leading to the weight gain characteristic of obesity. In an experiment regarding the genetic mutation of a gene called MRAP2 in mice, researchers found that the gene regulates the body's energy use and storage. Without this function — say, if the gene were mutated — one's appetite increases, energy usage decreases, and the animal gains a good deal of weight.

But wouldn't eating less ameliorate weight gain, regardless of genetics?

The gene, when functioning appropriately, signals to the brain and other related genes to tell the body it is no longer hungry. As a result, energy is burned, appetite suppressed, and dangerous weight gain avoided. However, when MRAP2 is mutated, it cannot perform this function and so the body tries to store as much energy as possible; this leads to overeating, as the body is never told it is full.

Researchers created mice without MRAP2 to observe weight gain throughout their life. The mice grew to about twice their normal size. The weight gain was more pronounced in males than females. Surprisingly, while the mice born without MRAP2 didn't eat more at first, they still gained weight more quickly than those with functioning MRAP2 genes. When monitored over 50 consecutive days, researchers discerned that these mice simply ate much more than the mice without the mutation in MRAP2. As they got older, their appetites increased and they continued to gain weight, even when held to the same diet and quantity of food as those without the MRAP2 mutation.

In order to test whether a mouse with this mutation could potentially get to a healthy weight, researchers put mice with and without the mutation on similar diets until they found that the two weighed almost the same. Notably, in the end, the mutant mice had to be underfed by 10 to 15 percent to show the same weight gain as their unmutated peers — though, as soon as they were let off the restricted diet, their weight gain increased rapidly.

This is noteworthy, as genetics have not been previously explored as an explanation for obesity. However, the findings regarding this genetic mutation are hard to ignore. Similarly, in a comparison of 500 genomes from a sample of severely obese humans, the researchers found one person with a disruptive mutation in the MRAP2 gene and four people with only some of their gene mutated, suggesting this mutation causing serious weight gain in mice might be a rare cause of obesity in humans.

"These mice aren't burning the fat, they're somehow holding onto it," said the study's lead investigator, Joseph Majzoub, M.D., chief of endocrinology at Boston Children's Hospital. "Mice with the genetic mutation gained more weight, and we found similar mutations in a cohort of obese humans."

But how did this gene's operation arise?

The "thrifty-gene hypothesis" explains that rare gene mutations that alter appetite and weight gain like MRAP2 exist because they gave humans an evolutionary advantage in times of severe famine before civilization was established. When food was scarce, those who could eat more and store that energy the few times they did find food would be able to survive better than those who could not store energy. Further investigation into how these mutations work may lend insight into the body's mechanisms for energy storage and use. In the present study, the lab did not observe anything to explain why the mutant mice were storing more food energy.

What are the implications?

Majzoub and his colleagues intend to expand the scope of their research by studying additional populations of obese people, including measures of their activity and diet, as well as further exploring how the gene alters energy usage in the body. However, the finding in mice and related finding in humans make the conclusion of this study clear: obesity can have a genetic basis.

Source: Asai M, Ramachandrappa S, Joachim M, et al. Loss of Function of the Melanocortin 2 Receptor Accessory Protein 2 Is Associated with Mammalian Obesity. Science. 2013.