Beige fat 'indispensable' in protecting the brain from dementia

Date:
August 10, 2021
Source:
Medical College of Georgia at Augusta University
Summary:
Beige is considered a calming paint color, and scientists have
new evidence that beige fat has a similar impact on the brain,
bringing down the inflammation associated with the more common
white fat and providing protection from dementia.



FULL STORY ========================================================================== Beige is considered a calming paint color, and scientists have new
evidence that beige fat has a similar impact on the brain, bringing down
the inflammation associated with the more common white fat and providing protection from dementia.


==========================================================================
They have found that beige fat cells, which are typically intermingled
with white fat cells in the subcutaneous fat present on "pear shaped"
people, mediate subcutaneous fat's brain protection, Dr. Alexis
M. Stranahan and her colleagues report in the journal Nature
Communications.

Pear-shaped people, whose weight is generally distributed more evenly,
rather than "apple shaped" individuals with fat clustered around their
middle and often around internal organs like the liver in the abdominal
cavity, are considered less at risk for cardiometabolic problems like
heart disease and diabetes, as well as cognitive decline, says Stranahan, neuroscientist at the Medical College of Georgia at Augusta University.

Now the scientists have shown that beige fat cells, or adipocytes, are "indispensable" to the neuroprotective and anti-inflammatory effects of subcutaneous fat, says Stranahan, the study's corresponding author.

In fact without beige adipocytes, in the face of a high-fat diet,
they saw subcutaneous fat start acting more like dangerous visceral
fat, says Stranahan who reported last year in The Journal of Clinical Investigationthat 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 says.

Visceral fat around the organs is mostly white fat cells, which
store energy as triglycerides, which are yet another fat type found
in the blood, and a risk factor for heart disease and stroke at high
levels. Particularly in younger people, subcutaneous fat is a mixture
of white and beige fat cells, and these beige cells are more like brown
fat cells, which are packed with powerhouses called mitochondria and are efficient at using fat and sugars to produce heat in a process called thermogenesis. Exercise and cold exposure are said to enable the so-called "beiging" of white fat cells.



==========================================================================
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.

On a high-fat diet, it's already been shown that 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 their metabolic profile in a few weeks, and she wanted to know
about potential impact on cognitive problems.

While both the normal and knockout mice gained about the same amount
of weight over four weeks, mice without functional beige fat displayed accelerated cognitive dysfunction on testing, and their brains and
bodies indicated a strong, rapid inflammatory response to the high-fat
diet that included activation of microglial cells, those resident immune
cells in the brain, which can further heighten inflammation and contribute
to dementia and other brain problems.

Before they ever developed diabetes, the microglia of the mice, whose
ages were comparable to a 20-something-year-old, had already turned on
numerous inflammatory markers. Interestingly normal mice they studied
as controls 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 a high-fat diet to show the
kind of responses they saw in the beige-fat knockouts in a single month.



==========================================================================
To further explore the impact of beige fat, they also 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 a high-fat diet for 10 to
12 weeks.

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,
the center of learning and memory deep in the brain. These positive
changes were dependent on the beige adipocytes in the donor subcutaneous
fat, Stranahan and her colleagues write.

Transplants from the beige-fat knockouts on the other hand did not
improve cognition in the obese mice, including by strictly objective
measures like any increased electrical activity between neurons.

"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,"
Stranahan says.

All fat tends to be packed with immune cells, which can both promote
and calm inflammation. They found beige fat interacts continuously with
those immune cells, inducing the anti-inflammatory cytokine IL-4 in the subcutaneous fat.

IL-4 in turn is required for cold to stimulate the "beiging" of fat,
she notes.

Also in turn, the fat induced IL-4 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. They also found T cells in
the choroid plexus, where cerebrospinal fluid is produced, had calming
IL-4 induced.

Their findings suggest IL-4 is directly involved in communication between
beige adipocytes and neurons in the hippocampus, the scientists write.

"It's kind of like "Whisper Down the Lane" if you ever played that
at camp," Stranahan says of what appears to be a calming chain of communication.

When Stranahan and her team looked further they found it was the
recipient's own T cells in the meninges that were called to positive, protective action by the transplanted beige fat cells, not immune cells
from the transplanted fat itself.

There is evidence that in chronic obesity, your 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.

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

Her many next 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 they 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 says.

The stage of obesity may be another factor, because she also has early
evidence suggesting that the longer a high-fat diet 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 notes.

Stranahan emphasizes that she does not want her findings to cause
excessive concern in overweight individuals or generate more prejudice
against them, rather the work is about better identifying risk factors
and different points and methods of intervention to fit the needs of individuals.

Stranahan and her colleagues reported in 2015 in the journal Brain,
Behavior, and Immunitythat a high-fat diet prompts microglia to become uncharacteristically sedentary and to start eating the connections
between neurons.

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 to 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, she says.

The research was funded by the National Institutes of Health.

========================================================================== Story Source: Materials provided by Medical_College_of_Georgia_at_Augusta_University.

Original written by Toni Baker. Note: Content may be edited for style
and length.


========================================================================== Journal Reference:
1. De-Huang Guo, Masaki Yamamoto, Caterina M. Hernandez, Hesam
Khodadadi,
Babak Baban, Alexis M. Stranahan. Beige adipocytes mediate the
neuroprotective and anti-inflammatory effects of subcutaneous
fat in obese mice. Nature Communications, 2021; 12 (1) DOI:
10.1038/s41467-021- 24540-8 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2021/08/210810104656.htm

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