Males of essentially any age have a greater
propensity to deposit fat around the major organs in their abdominal cavity,
called visceral adiposity, which is known to be far more inflammatory. And,
before females reach menopause, males are considered at much higher risk for
inflammation-related problems from heart attack to stroke.
Females’ propensity to deposit more fat in
places like their hips, buttocks and the backs of their arms, so-called
subcutaneous fat, is protective against brain inflammation, which can result in
problems like dementia and stroke, at least until menopause, scientists report.
“When people think about protection in women,
their first thought is estrogen,” says Alexis M. Stranahan, PhD, neuroscientist
in the Department of Neuroscience and Regenerative Medicine at the Medical
College of Georgia at Augusta University. “But we need to get beyond the kind
of simplistic idea that every sex difference involves hormone differences and
hormone exposure. We need to really think more deeply about the underlying
mechanisms for sex differences so that we can treat them and acknowledge the
role that sex plays in different clinical outcomes.”
Diet and genetics are other likely factors
that explain the differences broadly assigned to estrogen, says Stranahan,
corresponding author of a study in the American Diabetes Association journal
Diabetes.
She acknowledges that the findings are
potentially heretical and revolutionary and certainly surprising even to her.
“We did these experiments to try and nail down, first of all, what happens
first, the hormone perturbation, the inflammation or the brain changes.”
To learn more about how the brain becomes
inflamed, they looked at increases in the amount and location of fat tissue as
well as levels of sex hormones and brain inflammation in male and female mice
at different time intervals as they grew fatter on a high-fat diet.
Since, much like with people, obese female
mice tend to have more subcutaneous fat and less visceral fat than male mice,
they reasoned that the distinctive fat patterns might be a key reason for the
protection from inflammation the females enjoy before menopause.
They found again the distinctive patterns of
fat distribution in males and females in response to a high-fat diet. They
found no indicators of brain inflammation or insulin resistance, which also
increase inflammation and can lead to diabetes, until after the female mice
reached menopause. At about 48 weeks, menstruation stops and fat positioning on
the females starts to shift somewhat, to become more like males.
They then compared the impact of the high-fat
diet, which is known to increase inflammation body wide, in mice of both sexes
following surgery, similar to liposuction, to remove subcutaneous fat. They did
nothing to directly interfere with normal estrogen levels, like removing the
ovaries.
The subcutaneous fat loss increased brain
inflammation in females without moving the dial on levels of their estrogen and
other sex hormones.
Bottom line: The females’ brain inflammation
looked much more like the males’, including increased levels of classic
inflammation promoters like the signaling proteins IL-1β and TNF alpha in the
brain, Stranahan and her colleagues report.
“When
we took subcutaneous fat out of the equation, all of a sudden the females’
brains start to exhibit inflammation the way that male brains do, and the
females gained more visceral fat,” Stranahan says. “It kind of shunted
everything toward that other storage location.” The transition occurred over
about three months, which translates to several years in human time.
By comparison, it was only after menopause,
that the females who did not have subcutaneous fat removed but did eat a
high-fat diet, showed brain inflammation levels similar to the males, Stranahan
says.
When subcutaneous fat was removed from mice on
a low-fat diet at an early age, they developed a little more visceral fat and a
little more inflammation in the fat. But Stranahan and her colleagues saw no
evidence of inflammation in the brain.
One take-home lesson from the work: Don’t get
liposuction and then eat a high-fat diet, Stranahan says. Another is: BMI,
which simply divides weight by height and is commonly used to indicate
overweight, obesity and consequently increased risk of a myriad of diseases, is
likely not a very meaningful tool, she says. An also easy and more accurate
indicator of both metabolic risk and potentially brain health, is the also
easy-to-calculate waist to hip ratio, she adds.
“We can’t just say obesity. We have to start
talking about where the fat is. That is the critical element here,” Stranahan
says.
She notes that the new study looked
specifically in the hippocampus and hypothalamus of the brain. The hypothalamus
controls metabolism and exhibits changes with inflammation from obesity that
help control conditions that develop bodywide as a result. The hippocampus, a
center of learning and memory, is regulated by signals associated with those
pathologies but doesn’t control them, Stranahan notes. While these are good
places to start such explorations, other regions of the brain could respond
very differently, so she is already looking at the impact of loss of
subcutaneous fat in others. Also, since her evidence indicates estrogen may not
explain the protection females have, Stranahan wants to better define what
does. One of her suspects is the clear chromosomal differences between the XX
female and the XY male.
Stranahan has been studying the impact of
obesity on the brain for several years and is among the first scientists to
show that visceral fat promotes brain inflammation in obese male mice, and,
conversely, transplanting subcutaneous fat reduces their brain inflammation.
Females also have naturally higher levels of proteins that can tamp down
inflammation. It’s been shown that in males, but not females, microglia, immune
cells in the brain, are activated by a high-fat diet.
She notes that some consider the reason that
females have higher stores of subcutaneous fat is to enable sufficient energy
stores for reproduction, and she is not challenging the relationship. But many
questions remain like how much fat is needed to maintain fertility versus the
level that will affect your metabolism, Stranahan says.
Reference:
Alexis M. Stranahan et al, Sex Differences
in Adipose Tissue Distribution Determine Susceptibility to Neuroinflammation in
Mice With Dietary Obesity,JOURNAL
Diabetes