Export Of Damaged Mitochondria To The Heart May Explain ‘Obesity Paradox’

By Deborah Borfitz 

October 12, 2021 | Exosomal trafficking from fat to heart cells may help explain the “obesity paradox,” the baffling observation that packing extra pounds can have a beneficial, if short-term, protective effect for patients with heart disease. The cargo being delivered are oxidatively damaged mitochondrial particles that appear to prompt the heart to produce a flood of protective antioxidant molecules, better preparing it to cope with insults that later come along—such as a heart attack, according to Philipp E. Scherer, Ph.D., professor of internal medicine and cell biology at UT Southwestern Medical Center. 

The surprising discovery of this new “communication axis” between adipocytes and cardiomyocytes is described by Scherer and his colleagues in a recently published article in Cell Metabolism (DOI: /10.1016/j.cmet.2021.08.002), based on a study in mice. When the animals were fed a high-fat diet and became obese, their fat cells began sending out extracellular vesicles filled with small pieces of dying mitochondria. Some of these mitochondrial snippets traveled through the bloodstream to the heart. 

This triggered a protective backlash so strong that it enabled mice to better weather an induced heart attack, with the rodents experiencing less ischemia reperfusion injury. Similar effects might be expected in humans, based on follow-up experiments using fat tissue sampled from obese patients showing these cells also release mitochondria-filled extracellular vesicles, Scherer says. 

The metabolic stress of obesity gradually makes fat tissue dysfunctional, causing its energy-generating mitochondria to shrink and die. Eventually, the unhealthy fat tissue loses the ability to store lipids that flood the system due to excess calorie intake which in turn poisons other organs, he explains. 

Some organs appear to mount a preemptive defense to protect against the damage induced by lipids, referred to as lipotoxicity. But how the heart senses fat’s dysfunctional state has been unknown, says Scherer.  

Many Caveats 

The obesity paradox, first described in 2002, doesn’t change the fact that obesity predisposes people to cardiovascular disease, says Scherer, who has been studying fat metabolism for many years. It only means that they have a better chance of survival over the near term and it is “a bit of counterintuitive” why that is. 

Back in the 1980s, fat tissue was viewed as a relatively inert storage compartment for energy, he says. Its primary role was thought to be the absorption of excess calories after a meal and release of excess calories with prolonged fasting. It wasn’t until the mid-1990s that scientists began to realize that fat tissue is an endocrine organ whose role is to indicate to other organs how much fat storage is in the system. 

Scherer is among scores of researchers who have spent a lot of time looking at two specific mediators of communication between fat cells and heart tissue—the protein hormones leptin and adiponectin. 

Leptin “tells the brain how much energy is available in the system,” he says, so people know to eat less and exercise more to reach their ideal set point. “The more obese we are, the more leptin is in circulation.” 

Adiponectin is also highly specifically produced by fat cells, Scherer continues, but its level in the blood lowers as the pounds go on. It is a “good factor” seen in individuals with a lean body mass as well as the metabolically healthy obese—a subgroup of people with obesity who do not exhibit overt cardiometabolic abnormalities. 

Although not tied to the obesity paradox, being a tad overweight is also unexpectedly beneficial to people (particularly women) after age 70, he adds. Research suggests they live longer than their slimmer counterparts. 

It’s admittedly confusing given all the caveats. The concept of metabolically healthy obesity means some people can “apparently completely avoid any of the secondary consequences [including increased risk of cardiovascular disease, diabetes, and fibrosis]” long associated with an excessive amount of body fat, says Scherer. For yet unknown reasons, they can “expand that fat tissue in a healthy way,” thereby avoiding the deposition of lipids in the heart as well as other organs such as the liver.    

But as they age, the metabolically healthy obese become less invincible. While as many as 30% of people in their 20s with a body mass index in the mid to upper 30s might fit the phenotype, the proportion shrinks with the passing years, he says.  

Cellular Garbage Bins 

A new wrinkle was added to the story a few years ago with the discovery that fat cells can produce exosomes, says Scherer. Cancer researchers have embraced these small vesicles as vehicles for shuttling tumor biomarkers and anti-tumor drugs, but in the metabolism world, they have up until now not been well studied.  

Scherer and his colleagues not only showed that they exist in fat tissue, but that fat tissue is the “single most important source of exosomes in circulation,” he says. Their cargo includes many different proteins that fat cells produce, but they are “especially rich” in lipids that are signaling rather than energy-providing.  

The fact it is now known that these vesicles can contain mitochondrial particles that get delivered to the heart is “novel and intriguing,” Scherer continues. Mitochondria, which generate most of the cell’s supply of adenosine triphosphate (ATP, used as a source of chemical energy), are also integral to oxidative stress. 

Given way too much fuel—eating a fatty meal, for example—mitochondria can go into overdrive, he says, “but if there is not enough need for that kind of energy [ATP], the system kind of backs up” and free radicals are produced that damage both the cells and their mitochondrial cargo. 

Fat cells use exosomes as “cellular garbage bins” for the damaged mitochondrial particles, explains Scherer, likening it to Manhattan shipping its trash over to New Jersey. The UT Southwestern research team initially thought this was simply because the cells couldn’t cope with the waste material inside its own boundaries, but it turns out this exporting activity had a measurable impact on the heart. 

Although damaged, mitochondrial particles are still somewhat functional and when released induce a burst of “reactive oxygen species” that sets off alarm bells and puts the heart in a heightened state of oxidative stress. Pre-exposure to these exosomes better prepares the heart for the next wave of stress that strikes. 

Next Steps 

The long-term goal is to test “pre-conditioned exosomes” that have experienced a bit of oxidative stress as a potential treatment for human heart disorders, irrespective of whether they are induced by obesity, says Scherer. Potentially, it might also be used to confer cardioprotective effects on the morbidly obese undergoing surgery who are at higher risk of complications from anesthesia. 

Currently, the research team is focused on developing tools to “genetically turn off the spigot” of exosomes leaving fat cells and see how the heart responds to stress, he says, adding that stopping the exosomal flow is quite difficult to do in intact mice. But it’s an accomplishment that would improve scientific understanding of what exosomes are doing at the level of the heart cell—and perhaps other cell types, including the liver and muscles.