A new study in mice shows that immune cells in the brain can trigger overeating and weight gain in response to diets rich in fat.
Neurons within a region at the base of the brain known as the mediobasal hypothalamus (MBH) are known to regulate food intake and energy expenditure, and have been a target for the development of drugs to treat obesity.
The new study published online this week in Cell Metabolism, however, 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.
"Microglia are not neurons, but they account for 10 to 15 percent of the cells in the brain," said Suneil Koliwad, assistant professor of medicine at the University of California, San Francisco, and a co-senior author of the study.
"They represent an untapped and completely novel way to target the brain in order to potentially mitigate obesity and its health consequences."
Researchers from UCSF Diabetes Center and the University of Washington (UW) Medical Center 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 diet.
The MBH normally attempts to match the number of calories ingested in food with energy need to maintain a healthy weight, but previous research has shown that dietary fats can throw off this balancing act.
To learn whether the multiplying microglia are a cause of overeating and obesity in the mice, rather than a result of their weight gain, 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.
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 UW team, led by Joshua Thaler, associate professor of medicine with the UW Medicine Diabetes Institute, genetically engineered mice to prevent microglia from activating inflammatory responses.
The team found that these mice ate 15 percent less and gained 40 percent less weight on a high fat diet, suggesting that the inflammatory capacity of microglia 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 they could use a drug to activate the inflammatory response of microglia.
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.
The result was a four-fold, namely 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," said Thaler, a co-senior author on the paper, which also suggests 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 plan to investigate how consumption of high-fat foods leads to the activation of microglia, and whether there are ways to block these signals.
