Neurons within a region at the base of the brain known as the hypothalamus, which
plays a crucial role in eating, have long been a target for the development of drugs
to treat obesity. But the new study suggests that brain-resident immune cells called
microglia could also be targets for obesity treatments that might avoid many side
effects of the obesity drugs currently in clinical use.
‘When people constantly eat rich, high-fat foods, chronic microglial
activation could produce a more permanent stimulation of neural circuits that
further increase high-fat food intake.’
"Microglia are not neurons, but they account for 10 to 15 percent of the cells in
the brain," said Suneil Koliwad, MD, PhD, assistant professor of medicine at the
UCSF Diabetes Center, and a co-senior author of the new study. "They represent an
untapped and completely novel way to target the brain in order to potentially
mitigate obesity and its health consequences."
Microglia Responsible for Diet-Driven Weight Gain
A brain region called the mediobasal hypothalamus (MBH) 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 our need for energy
to maintain a healthy weight, but previous research has shown that dietary fats can
drastically throw off this balancing act.
In the new study, the researchers fed mice a fast food-like diet rich in fat for
four weeks, which is known to cause microglia to expand in number and to trigger
local inflammation within the MBH. Mice fed such a diet also eat more food, burn
fewer calories, and gain more weight compared to mice eating a more healthy, low-fat
Koliwad's team at UCSF depleted the number of microglia in the MBH of mice on the
fatty diet by giving them an experimental drug, called PLX5622, which is made by
Plexxikon Inc., a Berkeley, California-based 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.
The University of Washington team, led by Joshua Thaler, MD, PhD, associate
professor of medicine with the UW Medicine Diabetes Institute, genetically
engineered mice to prevent microglia from activating inflammatory responses, and
found that these mice ate 15 percent less and gained 40 percent less weight on a
, suggesting that the inflammatory capacity of microglia itself is
responsible for the animals' overeating and weight gain.
They 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, leading to a four-fold (400 percent) increase in weight
gain compared to untreated mice on the same healthy diet.
"From 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 new paper.
Microglia Increases Appetite and Weight Gain
But Koliwad believes that there could be a more positive explanation for the fact
that microglia have evolved the ability to rapidly trigger increased appetite and
weight gain in response to a high-fat diet: rich food was only rarely available
during mammalian evolutionary history, and when it was available, it would be
advantageous for animals to stop hunting or foraging and focus on chowing down.
"Microglial responsiveness to dietary fats makes some sense from this evolutionary
perspective," Koliwad said.
"Fats 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 period of fasting, microglia may have
been essential in relaying the presence of this meal to those neurons that would
stimulate maximal appetite."
But in modern environments, in which high-fat food is continually available, 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, leading to the development of a vicious cycle."
Drugs Targeting Brain Inflammation Could Help Treat Obesity
In their new paper, the researchers also report that high-fat diets trigger
microglia to actively recruit additional immune-system cells from the bloodstream to
infiltrate the MBH. Once there, the new recruits shape-shift to take on features
similar to those of the brain's own microglia, augmenting 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 immunologic approaches--targeting bona fide microglia as well
as targeting cells in the blood with the capacity to enter the hypothalamus and take
on microglia-like functions.
The researchers next plan to further investigate how, exactly, consumption of
high-fat foods leads to the activation of microglia, and whether there are ways to
intervene to block these signals.
- Suneil Koliwad et al., Brain's immune cells may
drive overeating and weight gain, Cell Metabolism (2017).