Two identical twins can share nearly the same DNA and still end up with very different body weights. Data from 49 such pairs led researchers to CD300e, an immune receptor found at much higher levels in the fat tissue of the heavier twins.
The finding is not a weight-loss button. New experiments suggest CD300e acts more like a protective brake, helping immune cells handle excess fat and sugar and limiting some of the metabolic damage seen with obesity. The evidence comes from mice, human tissue, and human cells studied in the lab.
The twin clue
The clue came from a 2021 twin study completed at the University of Helsinki. It compared 49 identical twin pairs whose members differed in body mass, with the heavier twin weighing about 38 lbs. more on average.
Identical twins provide a useful natural comparison because their shared genetic blueprint reduces much of the usual genetic noise.
The earlier work found that excess weight disrupted fat tissue more strongly than muscle, with weaker cellular energy pathways and more inflammation linked to insulin resistance, fatty liver, and unhealthy blood fats.
CD300e stood out because it was higher in the heavier twins, while separate weight-loss research showed its levels falling as people lost weight. Was it simply a warning light, or was it helping the tissue defend itself?
Scientists involved in the CD300e research, which explored how an immune receptor may help regulate fat storage and protect metabolic health in obesity.
What CD300e does
CD300e is a receptor, meaning a protein on the surface of certain immune cells that receives signals from its surroundings. It is found mainly on myeloid cells, a broad group that includes macrophages, which act like a cleanup crew inside fat tissue.
Macrophages take in fats and sugars, process them, and help nearby fat cells stay balanced. Sara Coletta, who coordinated the work with Marina de Bernard at the University of Padua, said CD300e is “not simply a disease marker.”
The new experiments indicate that it supports the cells’ ability to handle nutrients and produce energy.
Mouse tests showed protection
To learn whether the receptor played an active role, the team studied male mice that lacked CD300e. After 16 weeks on a high-fat diet, those animals gained more weight than control mice, with the difference emerging after about six weeks.
Their fat cells grew larger, their livers stored more fat, and their bodies handled glucose and insulin less effectively. A second model that removed CD300e mainly from myeloid immune cells produced similar results, strengthening the link to macrophages.
Unexpectedly, the metabolic decline was not accompanied by a major rise in classic inflammatory signals. That shifted attention toward the cells’ fuel-handling machinery, a quieter failure that can still throw the whole system off balance.
The cellular engines slowed
Without CD300e, macrophages absorbed less fat and glucose. Their mitochondria, the tiny structures that turn nutrients into usable energy, also worked less efficiently. Think of a cleanup crew whose trucks are running out of fuel just as the workload grows.
The nearby fat cells then moved toward storing more fat and releasing less of it. In other words, the tissue became worse at managing an energy surplus, while the liver faced more strain and accumulated additional fat.
Human cells echoed the result
The human evidence was more limited. Direct comparisons of fat tissue used samples from three people with obesity and three lean controls, while blood-cell measurements involved 43 adults with obesity and 35 normal-weight participants.
Researchers found more CD300e on macrophages inside fat tissue, but not on circulating monocytes in the blood. That suggests local conditions within enlarged fat tissue prompt the receptor to rise as incoming immune cells mature into macrophages.
When the team reduced CD300e by more than half in human monocytes, the cells took up less fat and showed weaker AKT signaling, part of the system used to respond to insulin and nutrients. The pattern matched the mouse results, but it remained a laboratory experiment rather than a treatment test in people.
Why higher levels can help
So why was CD300e higher in the twin with obesity if it appears protective? The most likely explanation is compensation, much like calling in extra workers when trash starts piling up. As weight falls and the workload eases, the tissue may no longer need as much of the receptor.
That makes the phrase “obesity switch” useful but incomplete. CD300e does not appear to flip obesity on or off. In this study, removing it made weight gain and metabolic problems worse.
A target, not a treatment
The discovery points toward a different treatment strategy. Rather than focusing only on inflammation, future drugs might preserve the metabolic fitness of macrophages so they can keep processing fats and sugars inside expanding fat tissue.
But the work used male mice, the direct human tissue sample was small, and scientists still do not know exactly what activates CD300e.
For now, CD300e is not a shortcut to weight loss, and changing an immune receptor could have effects beyond body fat. It is a promising clue about why some fat tissue copes better than other fat tissue, even when genetics are nearly identical.
The full study was published in Cell Death & Disease.
