Can a fat gene such as ankyrin-B cause obesity?

Does This Gene Fuel Obesity?

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Summary: Can a gene fuel obesity? Variants of a gene called ‘ankyrin-B’ – a gene carried by millions of Americans – could cause individuals to put on pounds through no fault of their own.  [This article first appeared on LongevityFacts. Follow us on Reddit | Google+ | Facebook. Author: Brady Hartman]

We often attribute obesity to eating too much and exercising too little. However, the evidence is growing that at least some of our weight gain is predetermined by our genes. And if a simple genetic variant causes weight gain, then it’s a prime target for gene editing.

New research from the University of North Carolina suggests that variants in a gene called ankyrin-B, a gene carried by millions of Americans, could cause individuals to gain weight through no fault of their own.

The study in mice shows that the genetic variation causes fat cells to suck up glucose faster than normal, more than doubling their size. When you add the metabolic changes that accompany aging or a high-fat diet to the equation, obesity becomes all but inevitable. The paper was published in the November 13 Proceedings of the National Academy of Sciences.

Vann Bennett, MD, Ph.D. is a senior author of the study and a Professor of Biochemistry at the Duke University School of Medicine. Speaking of the study’s findings, Bennett says,

“We call it fault-free obesity,” adding “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.”

Dr. Bennett discovered the protein ankyrin-B more than three decades ago. The protein is present in every tissue in the body and acts as an anchor by tethering essential proteins to the inside of the cellular membrane. Bennett and other scientists have linked defects in ankyrin-B to some human diseases, including muscular dystrophy, aging, diabetes, autism, and an irregular heartbeat.

Several years ago, Jane Healey, a student working in Dr. Bennett’s lab, noticed that mice with cardiac arrhythmia caused by mutations in ankyrin-B were fatter than their normal littermates. To figure out why she created mouse models that carried a couple of common human variants of the gene.

Damaris Lorenzo, Ph.D., a postdoctoral fellow in the lab at the time, discovered that these mice quickly grew fat. Instead of burning calories by sending them to energy-consuming tissues, these mutant mice locked most of their calories away in fat tissue. The researchers published their findings in 2015 in the Journal of Clinical Investigation (JCI). Speaking, of the JCI study, Dr. Bennett said,

“The problem is, we still didn’t know how this gene worked,” adding”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, Lorenzo, had her research group completely knock out the ankyrin-B gene in the fat tissue of mice and repeated the same experiments on the mice that carried mutant versions of ankyrin-B. Just as with the mutant mice, the knock-out mice gained weight, and their white fat cells, responsible for storing energy, doubled in size despite the fact that the mice were eating and exercising the same as normal ones. Moreover, the weight gain increased as the mice grew older or were fed a high-fat diet. Dr. Lorenzo said,

“We quickly learned that the increased accumulation of lipids in fat cells ‘spilled over’ to the liver and muscles,” adding,  “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.”

Fat cells showing ankyrin B-GLUT4 complexes (red dots).
Fat cells showing ankyrin B-GLUT4 (red dots). Credit: Courtesy of Damaris N. Lorenzo

After conducting some biochemistry experiments, Dr. Lorenzo showed that eliminating or mutating ankyrin-B changed the dynamics of Glut4, the protein that allows glucose to enter fat cells. The mutation opened the floodgates, allowing sugar to flow into the cells more quickly than normal.

Dr. Lorenzo wondered if the same mechanism held true for other known human mutations of ankyrin-B. Variants in are carried by About 1.3 percent of Caucasians, and 8.4 percent of African Americans carry variants in ankyrin-B,  amounting to millions of individuals in the United States. Lorenzo cultured fat cells carrying the variants and found that they too sucked up sugar at a higher rate. The condition seems to originate in fat tissue, although it likely affects other parts of the body. Discussing the finding, Dr. Bennett said,

“We found that mice can become obese without eating more, and that there is an underlying cellular mechanism to explain that weight gain,” adding, “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, Bennett says the team must confirm their laboratory findings in the general population. To do so, the researchers will first need to identify individuals with ankyrin-B variants, and then assess family histories, height and weight, and physiological traits as well as glucose metabolism, to determine the impact of these genetic variants on human health.

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References

Cover photo: Getty Images.

University of North Carolina Health Care System. “Does this one gene fuel obesity?.” ScienceDaily. ScienceDaily, 15 November 2017. Link

Damaris N. Lorenzo, Vann Bennett. “Cell-autonomous adiposity through increased cell surface GLUT4 due to ankyrin-B deficiency.” Proceedings of the National Academy of Sciences, 2017; 201708865 DOI: 10.1073/pnas.1708865114. Link.

Disclaimer

Diagnosis, Treatment, and Advice:  This article is intended for educational and informational purposes only and is not a substitute for qualified, professional medical advice.  The information and opinions provided herein should not be used during any medical emergency or for the diagnosis or treatment of any medical condition.  Consult a licensed and qualified physician for the diagnosis and treatment of any and all medical conditions. Call 911, or an equivalent emergency hotline number, for all medical emergencies. Moreover, consult a licensed physician before changing your diet, supplement or exercise programs. Endorsements, Photos, & External Links:  This article is not intended to endorse organizations, companies, or their products. Links to external websites, depiction or mention of company names or brands, are for illustration only and do not constitute endorsements.

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