Fat Cell Gene Deficiency Promotes Obesity

UNC School of Medicine’s Damaris Lorenzo, PhD, and colleagues show how a gene variant can trigger obesity in mice – without them eating more than control mice – and lead to health concerns related to weight gain.

Fat Cell Gene Deficiency Promotes Obesity click to enlarge Damaris Lorenzo, PhD
Fat Cell Gene Deficiency Promotes Obesity click to enlarge 3D confocal image of differentiated fat cells showing ankyrin B-GLUT4 complexes (red isosurface dots) decorating the plasma membrane. Isosurface of lipid droplets and nuclei in gold and in blue, respectively. (Courtesy of Damaris N. Lorenzo)

November 13, 2017

CHAPEL HILL, NC – Obesity is commonly attributed to eating excess calories we fail to burn. Consequently, overeating and a sedentary lifestyle have long been thought to be the chief culprits in the obesity epidemic. However, mounting evidence shows that certain genes can make people more susceptible to becoming obese. Adding to the list, new findings from research conducted at Duke University and UNC-Chapel Hill implicate mutations in a gene called ankyrin-B, which is carried by millions of Americans and now thought to predispose people to obesity. 

The study, which was conducted in mouse models, shows that a faulty ankyrin-B gene causes fat cells to uptake glucose faster than normal. This glucose overutilization causes fat cells to accumulate more lipids, which leads to the cells growing to more than double their normal size. As these mice that lack ankyrin-B in fat cells grow and age – or when fed a high-fat diet – they become inevitably obese. The findings were published online this week in Proceedings of the National Academy of Sciences.

Ankyrin-B was discovered over 30 years ago by senior author Vann Bennett, MD, PhD, the George Barth Geller Professor of Biochemistry at the Duke University School of Medicine. This protein, which is  present in virtually every tissue in the body, acts like an anchor by tethering important proteins to the inside of the cell’s membrane. Defects in ankyrin-B have been implicated in several human diseases, including autism, muscular dystrophy, aging, diabetes, and irregular heartbeat.

“Prior to our PNAS study, we knew that mice with deficient ankyrin-B genes have the tendency to becoming obese, but because ankyrin-B plays roles in other organs involved in metabolism, we could not unequivocally pinpoint the origin of this defect”, said first author Damaris Lorenzo, PhD, assistant professor of cell biology and physiology in the UNC School of Medicine. Lorenzo and colleagues had studied the metabolic syndrome developed by mice carrying the same ankyrin-B mutations found in people suffering from cardiac arrhythmia. These findings were published in 2015 in the Journal of Clinical Investigation.

 “Fat tissue is part of the metabolic axis, which also includes the liver, muscle, the pancreas, and the brain, all of which are in constant physiological cross-talk. Because of this, it’s common for issues appearing in one organ to have their origins in another. This tends to complicate the study of metabolic diseases, such as obesity and diabetes, but also makes it immensely interesting,” said Lorenzo, who is also a member of the UNC Nutrition Obesity Research Center (NORC) and the UNC Neuroscience Center. “Making matters more complicated is the fact that ankyrin-B plays roles in all these tissues, some of which we have yet to discover.”  

To sort this out, Lorenzo knocked out the ankyrin-B gene only in the fat tissue of mice. Like the mice with the mutated gene everywhere in the body, the mice lacking ankyrin-B in fat tissue also gained weight over time or when fed a high fat diet, and suffered from the same metabolic derailments. This result suggested that insufficiencies in the ankyrin-B gene in adipose tissue is sufficient to cause obesity.

“We quickly learned that the increased accumulation of lipids in fat cells “spilled over” to the liver and muscles,” she said. “The abnormal accumulation of fat in these tissues led to inflammation and disruption of response to insulin, a hallmark of type 2 diabetes. A similar cascade of events often takes place in humans, and that is why obesity can be so detrimental to our health.” 

After conducting several biochemistry experiments, Lorenzo showed that eliminating or mutating ankyrin-B changed the dynamics of Glut4, the protein that allows glucose to enter fat cells. This constituted another example of ankyrin-B’s involvement in intracellular transport of proteins, an important new role of ankyrin-B discovered by Lorenzo for the first time in neurons. The Lorenzo lab also studies neuronal cell biology and neurological diseases.

She wondered if the same mechanism held true for other known human mutations of ankyrin-B. About 1.3 percent of Caucasians and 8.4 percent of African Americans carry variants in ankyrin-B, accounting for millions of people in the United States alone. Using fat cells derived from mice carrying these variants, Lorenzo found that they, too, allow glucose into the cells at a higher rate.

“One of our immediate goals is to learn whether the same cellular defects take place in humans carrying these mutations, and whether they also lead to higher chances of developing obesity,” said Lorenzo. “If we confirm that this is indeed the case, we could identify at-risk individuals who can then become proactive about keeping their weight under control.”

Lorenzo says that they are collaborating with geneticists and epidemiologists to try to answer these questions.  

In parallel efforts, Lorenzo and her colleagues are currently studying the direct effects that ankyrin-B mutations have in other organs, which may simultaneously contribute to this metabolic syndrome. 

The research was supported by the Howard Hughes Medical Institute, the George Barth Geller Professorship fund, and a grant from the National Institute of Diabetes and Digestive and Kidney Diseases (P30DK056350) to the UNC Nutrition Obesity Research Center.

Media contact: Mark Derewicz, 984-974-1915, mark.derewicz@unchealth.unc.edu

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