Immune cells in the brain trigger overeating and weight gain in response to diets rich in fat, according to a study in mice. The research was led by scientists at UC San Francisco and at UW Medicine in Seattle. Their findings were published online in Cell Metabolism.
Read their paper. “Microglial inflammatory signaling orchestrates the hypothalamic immune response to dietary excess and mediates obesity susceptibility.”
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 eating.
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 of the obesity drugs currently in clinical use. Those side effects can include nausea, headache, dizziness,nervousness and insomnia.
“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. “They represent an untapped and completely novel way to target the brain in order to potentially mitigate obesity and its health consequences.”
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 hypothalamus. 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 weight gain. 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 Institute. 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 diet. The findings suggest that the inflammatory capacity of microglia itself is responsible for the animals’ overeating and weight gain.
To 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. 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. This lead 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 Cell Metabolism paper.
It may soon be possible to learn whether eliminating microglia can thwart weight gain in people as well. For 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.
The researchers also report that high-fat diets trigger microglia to actively recruit additional immune-system cells from the bloodstream to infiltrate the mediobasal hypothalamus. Once there, the new recruits morph to take on features similar to those of the brain’s own microglia. The 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 immunologic approaches. These 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 microglia-like functions.
The researchers 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.
Human 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.
This same sort of phenomenon, called gliosis, is commonly seen in neurodegenerative diseases, brain trauma, bleeding, infection and brain cancer. Some researchers suspect that dietary excess might essentially cause a form of brain injury.
But 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 diet. Rich 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,” 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 fast, microglia may have been essential in relaying the presence of this meal to those neurons that would stimulate maximal appetite.”
In 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 Family Fund.
Source: University of Washington