One of the main problems with obesity could be too few new fat cells for storage, forcing existing fat cells to engorge and become diseased, research at Augusta University has found.
The culprit appears to be an enzyme that is also implicated in cardiovascular diseases, an AU researcher said.
Dr. Neal Weintraub has a four-year, $1.8 million grant from the National Institutes of Health to study the enzyme in obesity and related functions. As a cardiologist, he sees the consequences in patients who are in their 20s and having a heart attack because they are obese and have related diseases such as diabetes.
Doctors used to be taught that the risk factors to watch for were smoking and high cholesterol, Weintraub said.
“Now, over the last few decades, this obesity epidemic has really changed the underlying mechanisms of cardiovascular disease,” he said. “Seldom do we see people with very high cholesterol any more that have cardiovascular disease. Instead, obesity has its own mechanisms, and really that’s what we are trying to identify.”
One of the breakthroughs in the lab came by accident, said Weintraub, the associate director of AU’s Vascular Biology Center. A researcher was having trouble getting precursor fat cells to differentiate and create new fat cells, he said. At first they thought he had made a mistake but then realized those fat cells came from an obese mouse, Weintraub said.
“That’s when we stumbled upon the observation that the cells just don’t differentiate properly,” he said. “When they can’t differentiate properly, the cells that are already mature have to take the full load of the excess caloric intake and they become over-enlarged and mechanically stressed.”
That can also lead to fat being deposited into the liver, which is a growing problem along with the obesity epidemic, Weintraub said.
“Once fat becomes stored in the liver, it is the main cause of liver disease,” he said.
Fat cells also serve a hormonal function, and those engorged fat cells become dysfunctional and help create inflammation and insulin resistance, which adds to cardiovascular problems.
The researchers then looked at a key regulator of fat cell differentiation called histone deacetylase 9 and found it wasn’t regulated properly in both obese mice and obese humans, Weintraub said. When mice are bred to not have the gene for it, they were not only protected from obesity but were also leaner, even when fed a high-calorie diet, he said.
“It turns out when we knocked this gene out, it turned the fat tissue into more of an energy-combusting tissue rather than an energy-storing tissue,” Weintraub said, creating more of what has been dubbed “beige fat.” That could be an important aspect, he said.
“(That) is really likely to be very important then for a target for obesity treatment,” Weintraub said. “There’s lots of interest in trying to figure out how do we actually convert fat from an energy storage tissue and organ into an energy-burning organ.”
The gene has been implicated directly in cardiovascular disease such as aneurysms and strokes, and the AU team is working with collaborators at Harvard University on those aspects, he said.
“Therefore it seems to be well-positioned to be in that sort of interface between obesity and cardiovascular disease,” Weintraub said.
One potential problem is that inhibitors of the enzyme don’t seem to work well, and that seems to be because it also goes into the nucleus of cells and binds with other proteins of the cells, which is where it could be affecting cell function, he said.
“Now we have to figure out exactly how does this mechanism work and could we target that binding mechanism,” Weintraub said. “There’s just a lot more to do. We are trying to unravel the mechanisms as the first step.”