Immune cells in the brain trigger overeating and
weight gain in response to diets rich in fat,
according to a study in mice.
Microglia (red) in the brain's hypothalamus monitor
their surroundings with spindly projections (Alice
Neurons within a region of the brain known as the
hypothalamus have long been a target for the
development of drugs to treat obesity. This area at
the base of the brain plays a crucial role in
But the new study suggests that brain-resident
immune cells called microglia could also be targets
for obesity treatments.
Targeting microglia instead of nerve cells might
avoid many side effects (include nausea, headache,
dizziness, nervousness and insomnia) of the obesity
drugs currently in clinical use.
“Microglia are not neurons, but they account for 10
percent to 15 percent of the cells in the
brain,”said Dr. Suneil Koliwad, assistant professor
of medicine at the UCSF Diabetes Center, and a
co-senior author of the report.
A brain region called the mediobasal hypothalamus
contains key groups of neurons that regulate food
intake and energy expenditure.
Normally, this region attempts to match the number
of calories ingested in food with the body’s need
for energy to maintain a healthy weight.
Previous research has shown that dietary fats can
drastically throw off this balancing act.
In the latest study, the researchers fed mice a diet
rich in fat for four weeks, similar to people
indulging in greasy fast-food.
A high-fat diet causes microglia to multiply and to
trigger local inflammation within the mediobasal
Mice fed such a diet also eat more food, burn fewer
calories, and gain more weight compared to mice
eating a healthier, low-fat diet.
The researchers wanted to learn whether the
multiplying microglia are a cause of overeating and
obesity in these mice, rather than a result of their
Koliwad’s team at UCSF depleted the number of
microglia in the mediobasal hypothalamus of mice on
the fatty diet by giving them the experimental drug
PLX5622, which is made by Plexxikon Inc., a
Berkeley, Calif., biotech company.
The researchers found that mice treated with the
drug ate 15 percent less and gained 20 percent less
weight than untreated mice on the same diet.
They still gained significantly more than mice fed
typical lab chow.
The drug treatment did not significantly affect
weight gain in mice on a normal lab chow diet.
The University of Washington School of Medicine team
was led by Dr. Joshua Thaler, an associate professor
of medicine who is with the UW Medicine Diabetes
His group genetically engineered mice to prevent
microglia from activating inflammatory responses.
They observed that these mice ate 15 percent less
and gained 40 percent less weight on a high fat
The findings suggest that the inflammatory capacity
of microglia itself is responsible for the animals’
overeating and weight gain.
Fluorescently labeled microglia (green) in the
mediobasal hypothalamus of the brain are responsive
to dietary conditions (John Douglass).
confirm this finding, the UCSF researchers developed
a strain of genetically engineered mice in which a
drug could be used to activate the inflammatory
response of microglia at will.
found that, even in mice fed a healthy, low-fat
diet, forcing microglia-induced inflammation in the
hypothalamus caused mice to eat 33 percent more food
and expend 12 percent less energy.
lead to a four-fold (400 percent) increase in weight
gain compared to untreated mice on the same healthy
these experiments we can confidently say that the
inflammatory activation of microglia is not only
necessary for high-fat diets to induce obesity, but
also sufficient on its own to drive the hypothalamus
to alter its regulation of energy balance, leading
to excess weight gain,” said Thaler, who was a
co-senior author on the Cell Metabolism paper.
may soon be possible to learn whether eliminating
microglia can thwart weight gain in people as well.
example, another drug made by Plexxikon, called
PLX3977, is currently in clinical trials for
hard-to-treat leukemias, solid tumors, and rare
forms of arthritis.
It acts by the same biological mechanism as PLX522,
the experimental drug the UCSF team used to reduce
microglia numbers in their recent project.
It may be possible to see whether cancer patients in
the PLX3977 trials experience beneficial effects on
body weight, Koliwad said.
researchers also report that high-fat diets trigger
microglia to actively recruit additional
immune-system cells from the bloodstream to
infiltrate the mediobasal hypothalamus.
there, the new recruits morph to take on features
similar to those of the brain’s own microglia.
additional troops augment the inflammatory response
and its impact on energy balance.
Therefore, the authors said, it may be possible to
control overeating and weight gain through multiple
can include targeting bona fide microglia as well as
directing efforts against cells in the blood with
the capacity to enter the hypothalamus and take on
brain-imaging studies in recent years have found
that, compared to lean individuals, people who are
obese are more likely to have expanded populations
of glial cells — the broader class of brain cells to
which microglia belong — in their hypothalamus.
same sort of phenomenon, called gliosis, is commonly
seen in neurodegenerative diseases, brain trauma,
bleeding, infection and brain cancer.
researchers suspect that dietary excess might
essentially cause a form of brain injury.
Koliwad has a more positive explanation for why
microglia have evolved to rapidly trigger increased
appetite and weight gain in response to a high-fat
food was only rarely available during mammalian
evolutionary history. When it was available, it
would be advantageous for animals to stop hunting or
foraging and to chow down.
“Microglial responsiveness to dietary fats makes
some sense from this evolutionary perspective,”
are the densest form of calories that ancient humans
might ever have had the opportunity to consume.
So, when primitive humans finally obtained a meal
after a long fast, microglia may have been essential
in relaying the presence of this meal to those
neurons that would stimulate maximal appetite.”
current times, this same adaptation can be damaging.
Koliwad said, “In our modern world, when people
constantly overeat rich, high-fat foods, chronic
microglial activation could produce a more permanent
stimulation of neural circuits that further increase
high-fat food intake and create a vicious cycle.”
Postdoctoral fellows Dr. Martin Valdearcos of UCSF,
and Dr. John D. Douglass, of the University of
Washington School of Medicine, conducted the
majority of experiments for the study, which was
funded by the American Diabetes Association, the
National Institutes of Health and the UCSF Diabetes
research was led by scientists at UC San Francisco
and at UW Medicine in Seattle. Their findings were
published online in Cell Metabolism.
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Microglial Inflammatory Signaling Orchestrates the
Hypothalamic Immune Response to Dietary Excess and
Mediates Obesity Susceptibility