New Genes IDd in Obesity: How Much of Weight is Genetic?

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In two separate papers, published in the journal Science and in the Journal of Clinical Investigation (JCI), researchers describe new genetic factors that could explain weight gain in some people. In the Science study, researchers at Boston Children’s Hospital studying mice found a rare genetic mutation that prevented the animals from burning off fat calories. They also found the same gene was mutated in a group of obese people. And a team based at University College London reported in JCI that a specific form of a gene previously linked to obesity, FTO, can increase craving for high-fat foods.

The discoveries add to the growing body of knowledge about the biology behind weight, and the results confirm that while it’s represented by a single number, weight is the complex combination of a multitude of different metabolic processes, from brain systems that regulate appetite to enzymes that control how efficiently calories are turned from food into energy that the body needs. Making matters even more confusing, these factors are also likely influenced by environmental contributors such as diet and lifestyle.

In the mouse study, the research team determined that mutations in the Mrap2 gene led the animals to eat less initially but still gain about twice as much weight as they normally would. While their appetites returned, these mice continued to gain weight despite being fed the same number of calories as a group of control animals. That led the scientists to figure out that the mice with the mutated gene were simply sequestering fat rather than breaking it down for energy. The mice, like people, possessed two copies of the gene, and mice with even one defective copy experienced significant weight gain, although not as much as those who had two mutated versions of Mrap2.

The scientists found a similar pattern among a group of 500 obese people; they detected four mutations in the human version of Mrap2, and each of the obese individuals possessed only one bad version of the gene.

(MORE: Study Identifies Four New Genetic Markers For Severe Childhood Obesity)

In the British study, the researchers divided a group of 359 healthy men of normal weight by their FTO gene status. The majority of the men had low-risk versions of the gene, while 45 of the participants had mutations that have been linked to greater appetite and caloric consumption. To figure out how the altered genes were affecting appetite, the team measured levels of the hunger hormone ghrelin both before and after meals that the participants ate; the men with the mutated form of FTO did not show the same drop in ghrelin levels, signifying that they were full, as the men with the low-risk form of FTO.

Genome wide association studies, which compare genetic makeups of obese individuals to those of normal weight, are making it easier to flesh out important genetic factors contributing to weight, and researchers at the Harvard School of Public Health say that to date, these studies have identified over 30 candidate genes on 12 chromosomes associated with body mass index.

“Thus far mutations in about eight genes are known to cause obesity in humans. But these mutations account for under five percent of the obesity in our society, and certainly are not, by themselves, responsible for the current obesity epidemic, since the mutation rate in these genes could not have changed dramatically during the past twenty years,” says Dr. Joseph Majzoub, the chief of the division of endocrinology at Boston Children’s Hospital and an author on the Science paper. “However, mutations in these genes have led to the discovery of pathways that are important in energy balance in humans, giving us hope that drugs can be developed that affect these pathways to prevent excessive weight gain, either by curbing appetite or increased burning of calories.”

(MORE: What Mice Can Tell Us About Obesity and Genetics)

Here is a round-up of some recent genes, and their products, that have been linked to obesity :

Leptin: Often referred to as the “obesity hormone,” leptin is made by fat cells and acts as a thermostat for the body’s energy needs. Each individual has his own leptin threshold; if leptin levels fall below that amount, the brain understands that the body is starving, and needs more calories. If leptin levels are maintained or surge above that amount, the brain knows that it doesn’t need to take in more food. Unfortunately, while mouse studies showed that overweight mice had lower levels of leptin, the same wasn’t true of obese people, who generally show higher levels of leptin in their blood. Somehow, researchers how believe, these people are not getting the signal to stop eating, which is referred to as leptin-resistance.

Ghrelin: This gene makes an appetite hormone that can make foods look more desirable–especially high-calorie ones — by influencing the brain’s reward system. Some studies have found that  people who are sleep-deprived have increased ghrelin levels, which may explain why lack of sleep can contribute to weight gain.

Neuropeptide Y: One of the brain’s many chemicals, neuropeptide Y may trigger eating by manipulating appetite, possibly resulting from changes in mood and stress levels. It may also contribute to an increased deposition of fat from food calories.
