If fat cells become metabolically stressed and dysfunctional, they start churning out chunks of mitochondria that serve as warning signals to the heart of potential catastrophe, suggest the authors of a paper published in Cell Metabolism today (August 20). The mitochondrial signals cause a burst of reactive oxygen species (ROS) in heart cells that seems to prime and protect the organ against future insult.
“It’s a fascinating observation,” says Scott Summers, a diabetes and metabolism researcher at the University of Utah who was not involved with the project. “I think we’re all going to be watching to see if this [mitochondrial shuttling] ends up being a major regulatory pathway by which organs change their behavior.”
“And the fact that they saw this as eliciting a protective effect in the heart,” he adds, “that’s pretty interesting.”
Fat not only helps to insulate and protect the body’s organs, it also stores energy and vitamins, and regulates appetite, metabolism, and immunity. Some of fat’s regulatory effects are achieved by secreting hormones such as leptin and adiponectin. But fat also communicates with organs via extracellular vesicles, small lipid-bound particles released from cells. In fact, of the extracellular vesicles found in the blood, around half derive from adipose tissue, says cell biologist Philipp Scherer of the University of Texas Southwestern Medical Center who led the new study.
He and his colleagues therefore considered extracellular vesicles to be the prime suspects behind an unexplained effect of fat on the heart they’d previously reported: when they stressed mouse adipose tissue—by engineering the fat cells to have overactive mitochondrial ferritin (a mitochondrial matrix enzyme) and feeding the animals a high-fat diet—oxidative stress levels in the heart, where mitochondria functioned normally, also ramped up.
Sure enough, the team finds in the new study that stressing mouse adipose tissue in this way causes the fat cells to release vast numbers of extracellular vesicles that travel to the heart. Furthermore, when these adipocyte-derived vesicles are added to cardiomyocyte cultures or injected into a mouse, they can enter heart cells and boost ROS-induced damage, a form of oxidative stress.
Examinations of the contents of the extracellular vesicles revealed “they had a striking number of mitochondrial proteins in them,” recalls Scherer. Further analysis indicated that although the vesicles likely contained only fragments of mitochondria, these particles were capable of generating ATP like their full-size intracellular counterparts.
The fat cell is full of surprises.—Philipp Scherer, University of Texas Southwestern Medical Center
The researchers “demonstrated release of mitochondria associated with extracellular vesicles from adipose tissue . . . and that’s provocative,” says Anthony Ferrante, who studies body fat at Columbia University and was not involved in the research. It “opens the field to look at these [vesicles]” in more detail, he says.
The team also analyzed plasma samples from human volunteers. They found that in plasma from obese, metabolically unhealthy individuals, a greater proportion of extracellular vesicles contained mitochondrial DNA than did vesicles from the plasma of lean people, suggesting that mitochondrial fragments may act as signals in humans too.
The finding that the vesicles cause oxidative stress in the heart might be considered a bad thing, and in the long term, it probably is, says Summers. But to their surprise, Scherer and his colleagues team found that a small dose of the ROS-boosting vesicles had a cardioprotective effect. When the researchers injected the vesicles or a control of saline into mice and then two hours later induced heart attacks in the animals, those that had received the vesicles fared better than the controls—they had smaller heart injuries and better preservation of heart function.
“It’s a case of preconditioning of the heart,” explains Scherer. “If you sprinkle in a little bit of reactive oxygen damage in the heart through these mitochondria, the heart mounts an anti-oxidant response and that . . . turns out to be vital” for protection against a potentially lethal heart attack.
That’s not to say that being obese is better for a person’s heart than being lean, Scherer is quick to point out. Obesity is a major risk factor for cardiovascular disease. The results do suggest, however, that in obese individuals, signals from body fat may help prepare the heart for likely problems, he says.
While questions remain over how cells regulate vesicle production and how these messages exert their effect, finding the answers is bound to be intriguing. After all, says Scherer, “the fat cell is full of surprises.”