Studies by scientists at the Medical College of Georgia, Augusta University, indicate that beige fat cells in subcutaneous fat play an important role in reducing inflammation associated with white fat, and offer the brain protection from dementia. Beige fat cells are typically intermingled with white fat cells in the subcutaneous fat present on “pear shaped” people. The team’s studies in mice found that these beige fat cells are “indispensible for the neuroprotective and anti-inflammatory effects of subcutaneous fat,” and implicate a potential role for interleukin-4 (IL4) in communication between beige fat and brain function. The experiments also showed that mice given transplants of subcutaneous fat were protected against chronic obesity via beige fat-dependent mechanisms.

The team, headed by neuroscientist Alexis M. Stanahan, PhD, reported on the studies in Nature Communications, in a paper titled, “Beige adipocytes mediate the neuroprotective and anti-inflammatory effects of subcutaneous fat in obese mice,” in which they concluded, “These findings indicate that beige adipocytes oppose obesity-induced cognitive impairment, with a potential role for IL4 in the relationship between beige fat and brain function.”

Visceral fat around the organs is mostly composed of white fat cells, which store energy as triglycerides, which are another fat type found in the blood, and represent a risk factor for heart disease and stroke at high levels. In contrast, and particularly in younger people, subcutaneous fat, or subcutaneous adipose tissue (SAT), is a mixture of white and beige fat cells, and these beige cells are more like brown fat cells, which are packed with mitochondria and are efficient at using fat and sugars to produce heat via thermogenesis. “Unlike visceral fat, which contains a homogeneous population of white adipocytes, subcutaneous fat contains both white adipocytes and ‘beige’ adipocytes that expend energy in a manner analogous to brown fat,” the authors wrote.

Exercise and cold exposure are said to enable the so-called ”beiging” of white fat cells. In adults, brown fat is primarily located between the shoulder blades and in the upper chest. Evidence suggests we can increase brown and beige fat cells by exposing ourselves to cooler or cold temperatures for several hours daily and through intense exercise. These approaches also can prompt the beiging of white fat. Most of us probably have some combination of fat cell types: mostly white, less beige, and even less brown, Stranahan said.

Pear-shaped people, whose weight is generally distributed relatively evenly, are considered less at risk for cardiometabolic problems like heart disease and diabetes, as well as cognitive decline, when compared with “apple shaped” individuals who have fat clustered more around their middle and often around internal organs such as the liver, Stranahan explained. And while there are relatively few fewer studies that have focused on subcutaneous adiposity and cognitive decline, data does suggest that the “pear-shaped” distribution of body fat doesn’t increase rates of mild cognitive impairment or dementia, and may, in fact, be protective. As the authors further noted, “Visceral adiposity at midlife predicts subsequent rates of dementia independently of weight loss during the intervening decades, suggestive of a critical window for dysfunction in the adult brain.”

Beige adipocytes interact with immune cells, and “beiging” is associated with the induction of anti-inflammatory cytokines IL4 in SAT. For their studies, the team investigated immunoregulatory interactions between beige adipocytes and cognition through a series of dietary obesity, and SAT transplantation experiments in male mice.

For some of their studies, the scientists used male mice with a specific gene knocked out that prevents adipocytes in the subcutaneous fat from beiging or browning, effectively resulting in subcutaneous fat that is more like visceral fat. It was already know that when fed a high-fat diet (HFD), these mice develop diabetes more rapidly than those with normal amounts of beige fat. It’s also known that transplanting subcutaneous fat into an obese mouse will improve metabolic profile in a few weeks. Stranahan wanted to know about potential impact on cognition.

Through their studies the team showed that while both the normal and the knockout mice gained about the same amount of weight over four weeks when fed on the HFD, animals without functional beige fat displayed accelerated cognitive dysfunction on testing, and their brains and bodies indicated a strong, rapid inflammatory response to the HFD that included activation of microglial cells, resident immune cells in the brain, which can further heighten inflammation and contribute to dementia and other brain problems. So without beige adipocytes, and in the face of an HFD, subcutaneous fat started acting more like dangerous visceral fat, said Stranahan.

Alexis Stranahan, PhD, and co-author immunologist Babak Baban, PhD. [Michael Holahan, Augusta University]
“Mice lacking beige adipocytes exhibited stronger pro-inflammatory responses to a HFD in the brain and periphery, and were more susceptible to cognitive deficits and hippocampal synaptic dysfunction,” the team noted. Stranahan reported last year that visceral adiposity sends a message to resident immune cells in the brain to fire up the inflammation, which ultimately damages cognition. “It’s a very different signature,” she said.

And even before they developed diabetes, the microglia of these mice—whose ages were comparable to a 20-something-year-old—had already turned on numerous inflammatory markers. Interestingly, the normal (wild-type; WT) control mice also turned on these markers, but turned on anti-inflammatory markers as well, apparently to minimize any response. Normally it takes mice about three months on an HFD to show the kind of responses that the researchers observed in the beige-fat knockouts in a single month.

To further explore the impact of beige fat, the team then transplanted subcutaneous fat from young, lean healthy mice into the visceral compartment of otherwise normal, but now-obese mice who had developed dementia-like behavior after remaining on an HFD for 10 to 12 weeks. They found that transplanting the subcutaneous fat resulted in improved memory, restoring essentially normal synaptic plasticity—the ability of the connections between neurons to adapt so they can communicate—in the hippocampus, which is the center of learning and memory deep in the brain. “Subcutaneous fat transplantation restored hippocampus-dependent memory in Wt recipients with dietary obesity and induced a unique microglial phenotype characterized by co-induction of pro- and anti-inflammatory markers,” the authors wrote. These positive changes appeared to be dependent on the beige adipocytes in the donor subcutaneous fat, as the team found that transplants from the beige-fat knockouts did not improve cognition in the obese mice, when assessed by strictly objective measures, such as any increased electrical activity between neurons.

Fat is packed with immune cells, which can both promote and calm inflammation. The Stranahan team found that beige fat interacts continuously with those immune cells, inducing the anti-inflammatory cytokine IL4 in subcutaneous fat. IL4, in turn, is required for cold to stimulate the beiging of fat, Stranahan noted. The investigators demonstrated that the fat also induced IL4 in microglia and T cells—key drivers of the immune response—in the meninges, a sort of multilayer cap that fits over the brain to help protect it. Additional experiments found that T cells in the choroid plexus, where cerebrospinal fluid is produced, had calming IL-4 induced effects. “Beige adipocytes were required for induction of IL4 among lymphocytes in the meninges and choroid plexus, and recipient-derived lymphocytes were required for the cognitive effects of SAT transplantation,” they commented. The findings suggest that IL-4 is directly involved in communication between beige adipocytes and neurons in the hippocampus.

“It’s kind of like ‘Whisper Down the Lane’ if you ever played that at camp,” Stranahan said of what appears to be a calming chain of communication. “If we can figure out what it is about beige fat that limits inflammation and maybe what it is about beige fat that improves brain plasticity, then maybe we can mimic that somehow with a drug or with cold-stimulated beiging or even taking out some of your subcutaneous fat when you are young, freezing it, and giving it back to you when you are older.”

When Stranahan and her team looked further they found it was the recipient’s own T cells in the meninges, and not immune cells from the transplanted fat, that were called to positive, protective action by the transplanted beige fat cells. There is evidence that in chronic obesity, the body’s own immune cells can reach the brain, and there was no evidence in this case that it was the donor’s immune cells making the journey. “There was no sign of donor-derived lymphocyte trafficking between fat and brain, but recipient-derived lymphocytes were required for the effects of transplantation on cognition and microglial morphology,” the team commented.

“It’s exciting because we have a way for peripheral immune cells to interact with the brain in a way that promotes cognition,” Stranahan said, noting that there also are many bad things immune cells could do in the brain like contribute to stroke and Alzheimer’s.

Her many goals include learning more about how much it matters where you put the transplanted fat, like whether transferring subcutaneous fat to a subcutaneous area might work even better to protect against cognitive decline; whether transplanting visceral fat to a subcutaneous area decreases its damaging effect; and better understanding how subcutaneous fat sends what appears to be an active anti-inflammatory message. She also wants to explore these issues in female mice since the current studies were limited to males. But what the Stranahan team and others already are finding underscores the importance of inherent fat distribution, which could be a biomarker for those most at risk for cognitive decline, she suggested.

The stage of obesity may be another factor, because she also has early evidence suggesting that the longer an HFD is maintained and the more subcutaneous fat increases, its protective powers decrease and visceral fat increases. Even in a healthy, non-obese young person visceral fat is going to produce higher levels of basal inflammation, Stranahan noted.

Stranahan and colleagues reported back in 2015 that a high-fat diet prompts microglia to become uncharacteristically sedentary and to start eating the connections between neurons. She emphasizes that she does not want the latest findings to cause excessive concern in overweight individuals, but rather considers the work is more about better identifying risk factors and different points and methods of intervention to fit the needs of individuals.

Previous articleMicroarchitecture and Insulin Responsiveness of Fat Cells Uncovered by Spatial Transcriptomics
Next articleMIS-C in Children May Be Driven by T-Cell Exhaustion