Gene mutation leads to fat storage and obesity!

Gene mutation leads to fat storage and obesity!

Obesity is often attributed to a simple equation: People are eating too much and exercising too little. But evidence is growing that at least some of the weight gain that plagues modern humans is predetermined.

New research suggests that variants in a gene called ankyrin-B -- carried by millions of Americans -- could cause people to put on pounds through no fault of their own.

The study, which was conducted in mice, shows that the gene variation causes fat cells to suck up glucose faster than normal, more than doubling their size. When an aging metabolism or high-fat diet is added to the equation, obesity becomes all but inevitable.

"We call it fault-free obesity," said senior author of the study. "We believe this gene might have helped our ancestors store energy in times of famine. In current times, where food is plentiful, ankyrin-B variants could be fueling the obesity epidemic." The results appear in the Proceedings of the National Academy of Sciences.

Ankyrin-B is present in every bodily tissue and acts like an anchor by tethering important proteins to the inside of the cell's membrane. The researchers have linked defects in ankyrin-B to a number of human diseases, including autism, muscular dystrophy, aging, diabetes and irregular heartbeat.

Researchers previously noticed that mice with cardiac arrhythmia caused by mutations in ankyrin-B were fatter than their wildtype litter mates. To figure out why, they created mouse models that carried a couple of common human variants of the gene. They found that these mice quickly grew fat, locking away most of their calories in fat tissue rather than sending them to other tissues to burn as energy. These findings were published in 2015 in the Journal of Clinical Investigation.

"The problem is, we still didn't know how this gene worked," said the senior author. "There is this common belief in the field that much of obesity can be traced back to appetite and the appetite control centers that reside in the brain. But what if it isn't all in our head?"

To study that question, researchers completely knock out the ankyrin-B gene in the fat tissue of mice.mThey repeated many of the same experiments that had been conducted in the previous mouse models, which carried mutant versions of ankyrin-B throughout their bodies. Like before, the knock-out mice gained weight, and their energy-storing white fat cells doubled in size -- despite eating and exercising the same amount as normal mice. What's more, the weight gain increased as the mice aged or were fed a high-fat diet.

"We quickly learned that the increased accumulation of lipids in fat cells "spilled over" to the liver and muscles," author said. "The abnormal accumulation of fat in these tissues led to inflammation and disruption of response to insulin, a hallmark of type II diabetes. A similar cascade of events is what often takes place in humans, and that is why obesity can be so detrimental to our health," author said.

After conducting a number of biochemistry experiments, researchers showed that AnkB binds directly to GLUT4 and clathrin and promotes their association in adipocytes. Eeliminating or mutating ankyrin-B changed the dynamics of Glut4, the protein that allows glucose to enter fat cells. . Impaired function of ankyrin-B (AnkB)  results in persistent cell surface glucose transporter type 4 (GLUT4) in adipocytes from the defective coupling GLUT4 to clathrin-mediated endocytosis. As a result, the flood gates were effectively opened, allowing glucose to flow into the cells more quickly than normal.

Authors wondered if the same mechanism held true for other known human mutations of ankyrin-B. Variants in ankyrin-B are carried by 1.3% of Caucasians and 8.4% of African Americans, accounting for millions of people in the United States alone. They cultured fat cells carrying these variants and found that they too sucked up glucose at a higher rate. The disease seems to originate in fat tissue, though it likely has effects elsewhere in the body.

"We found that mice can become obese without eating more, and that there is an underlying cellular mechanism to explain that weight gain," senior author said. "This gene could enable us to identify at-risk individuals who should watch what kind of calories they eat and exercise more in order to keep their body weight under control."

But first, the senior author says their findings in the laboratory must be confirmed in the general population. To do so, the researchers will need to identify individuals with ankyrin-B variants, and then assess family histories, height and weight, and characteristic physiological traits as well as glucose metabolism, to determine the impact of these variants on human health.