Rare Gene Mutations Suggest One More Path to Obesity

Mutations in the Mrap2 gene cause mice to become obese (left). A similar effect is seen in humans. (Image: Boston Children’s Hospital)

Mutations in the Mrap2 gene cause mice to become obese (left). A similar effect is seen in humans. (Image: Boston Children’s Hospital)

New research suggests that people with rare mutations of a gene linked with regulating metabolism may be highly susceptible to becoming obese.

The gene involved is known as Mrap2 in mice and as MRAP2 in humans. It’s expressed predominantly in the brain, in some of the regions that regulate energy balance. The gene encodes a protein that apparently is linked with increasing metabolism and decreasing appetite.

To examine the gene’s effect on weight gain, researchers at Boston Children’s Hospital first inactivated Mrap2 in mice. The mice appeared normal until they were about a month old. Then they started to gain more weight, became excessively hungry, and ate more than their siblings with Mrap2 intact.

Even when their food was restricted to the same amount as their normal siblings, mice with the inactivated gene still gained more weight. They didn’t gain weight at the same rate as their siblings until they ate 10% to 15% less food. Mice with both copies of Mrap2 inactivated gained the most weight, but even mice with 1 working copy of the gene gained more weight and had bigger appetites than the normal mice.

When allowed to eat freely, mice with the inactivated gene ate almost twice as much as their siblings. They had more visceral fat, which surrounds organs deep in the abdomen and is linked with cardiovascular disease, diabetes, and colorectal cancer. They also had more fat in their liver, according to the results published online today in the journal Science

“These mice aren’t burning the fat; they’re somehow holding on to it,” the study’s lead investigator, Joseph Majzoub, MD, said in a statement.

Majzoub, chief of endocrinology at Boston Children’s, noted that he and his collaborators found similar mutations in obese participants in the Genetics of Obesity Study, an international effort to determine why some people become severely obese at a young age. They found 4 rare MRAP2 mutations in 500 obese study participants, all who had 1 working copy of the gene.

Rare MRAP2 mutations lead to obesity in fewer than 1% of people with such severe weight problems, the researchers said. But they suspect that other, more common mutations occur in the gene and may interact with various genetic and environmental factors to cause more widespread forms of obesity. They plan to expand the scope of their research to examine that possibility.

A Bitter Pill May Be Just the Thing for Weight Loss

Bitter tastes trigger a cascade of events in the gut, a phenomenon that suggests new approaches in obesity treatment and prevention. (Image: Niilo Tippler/iStockphoto.com)

Bitter tastes trigger a cascade of events in the gut, a phenomenon that suggests new approaches in obesity treatment and prevention. (Image: Niilo Tippler/iStockphoto.com)

Does weight loss really have to be the proverbial bitter pill? Researchers in Belgium who’ve studied how receptors in the gut respond to sweet, salty, bitter, sour, and umami taste sensations say the answer may be yes—literally.

In a review article published online today in Trends in Endocrinology and Metabolism, investigators at the Catholic University of Leuven suggest that the gut’s bitter taste receptors could be high-quality targets for potential drugs aimed at preventing or controlling obesity.

The gut’s ability to detect bitter tastes probably plays a role in limiting the absorption of toxins. It may seem counterintuitive, but the investigators said bitter tastes also boost secretion of the appetite-stimulating hormone ghrelin. Eating a meal then slows ghrelin production. Subsequently, the stomach muscle relaxes and the stomach empties more slowly, so a tempting dessert doesn’t seem quite so inviting. Continue reading

Disrupting Body’s Biological Clock May Increase Risk of Weight Gain, Diabetes

Working at night and disrupting normal sleep patterns may increase the risk of weight gain and developing diabetes, a study suggests. (Image: Pedro Castellano/iStockphoto.com)

Disruption of circadian rhythm, the body’s internal biological clock, an experience familiar to night-shift workers and jet-lagged world travelers, appears to increase the risk of gaining unwanted pounds and developing diabetes. These findings are published online today in Science Translational Medicine.

Researchers at Brigham and Women’s Hospital in Boston cloistered 21 healthy participants in a completely controlled environment, during which their diet was kept constant and their activities were scheduled. Immediately before the study’s start, the participants spent 3 weeks at home getting adequate sleep at night. During the next 3 weeks in the controlled environment, they slept only 5.6 hours during every 24-hour period, and this shorter sleep period occurred 4 hours later on each subsequent day, simulating the schedules of rotating shift workers and travelers crossing time zones. The participants then spent 9 days again getting adequate sleep at night. Continue reading

Pythons Offer New Clues in Heart Disease

Leslie Leinwand, PhD, heads a research team at the University of Colorado, Boulder, that studies how python heart function could lead to new therapies for human heart disease. (Image: Thomas Cooper)

Pythons aren’t usually thought of as big-hearted creatures. But after a Burmese python feeds on a huge meal, its heart size swells and so does the quantity of fatty acids in its bloodstream. The process is a healthy one that scientists say could offer clues to help develop new treatments for human heart disease.

In today’s Science, a team led by researchers at the University of Colorado in Boulder shows that a day after a big feast, pythons’ heart mass can grow by 40%, their triglyceride levels shoot up more than 50-fold, and their metabolism speeds up 40-fold. Their heart tissue has higher activity of superoxide dismutase, an antioxidant enzyme known to protect the heart. Researchers found no evidence of fat deposits in the snakes’ hearts.

Similar increases in heart mass, triglycerides, and metabolism occurred when researchers injected snakes that hadn’t fed recently with blood plasma from well-fed pythons or a fatty acid mixture they made to mimic the plasma. Results were the same in mice injected with the python plasma or the fatty acid mixture. Cultured rat heart cells also responded similarly. Continue reading