Brain’s Immune Cells May Make You Fat: Study

Researchers have found that immune cells in the brain may trigger overeating and weight gain in response to diets rich in fat, according to a new study in mice published Wednesday in the journal Cell Metabolism. The researchers from the University of California, San Francisco, and the University of Washington Medical Center found a link between brain inflammation and obesity in mice.

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Obesity is common and growing in prevalence, especially in segments of the population worldwide that have poor access to healthy nutrition, affordable health care and optimal education to learn how to adopt a healthy lifestyle, says Dr. Suneil Koliwad, assistant professor of medicine at the UCSF Diabetes Center and the Gerold Grodsky chair in diabetes research at the university.

Drugs to treat obesity typically target neurons within a region at the base of the brain, called the hypothalamus—which controls functions like thirst and hunger. But those drugs often come with risks and unwanted side effects, such as depression or even suicidal thoughts. It’s not sufficient to tell patients to exercise more or eat less because there is “real biology” that leads to obesity, says Koliwad, co-senior author of the new paper. Koliwad tells Newsweek that he hopes to mitigate obesity and its consequences without the side effects that plague the drugs currently available to consumers.

The study suggests that microglia, which are brain-resident immune cells, could also be targets for obesity treatments. Microglia account for 10 to 15 percent of all cells found within the brain and act as the main form of active immune defense in the central nervous system. But until this study, Koliwad says, “it has not been clear at all whether these cells are responding to some sort of perceived insult or damage that occurs in the context of obesity, or whether they might be playing any role in actually causing obesity.”

One of the regions of the brain, referred to as the mediobasal hypothalamus (MBH), contains key groups of neurons that regulate food intake and energy expenditure. The MBH typically attempts to match the number of calories ingested in food with the human need for energy to maintain a healthy weight. But dietary fats can dramatically throw off this balance, as shown in previous research.

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 diet. Scientists found that fat-rich diets cause microglia to drive overeating and weight gain in mice.

0705_overweight_study_01 An overweight woman sits on a chair in New York City’s Times Square on May 8, 2012. A new study published Wednesday has found that immune cells in the brain trigger overeating and weight gain in response to diets rich in fat. Lucas Jackson/Reuters

To learn whether the multiplying microglia are a cause of overeating and obesity in the mice, Koliwad’s team 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. 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.

Other parts of the research focused on genetically engineered mice to prevent microglia from activating inflammatory responses. Researchers found that these mice ate 15 percent less and gained 40 percent less weight on a high fat diet. This outcome suggests that the inflammatory capacity of microglia itself is responsible for the animals’ overeating and weight gain, according to the study.

The researchers also report that high-fat diets trigger microglia to actively recruit additional immune-system cells from the bloodstream to infiltrate the MBH. They identify microglia as critical regulators of the hypothalamic control of energy balance, and believe these cells could be targeted in obesity.  

The findings show that activation of microglia can instruct the function of neurons involved in regulating food intake, energy expenditure and, therefore, body weight. “If you just activate microglia, they contain within them a specific signal that controls the circuitry that regulates body weight in the brain,” Koliwad tells Newsweek.

Before the study, scientists knew microglia are recruited to the hypothalamus and that their numbers increase in that area of the brain in the context of obesity. But what they’re doing in that context was not clear.

The team plans next to investigate what it is about human diets that stimulates the activation of the microglia in the hypothalamus and to define the specific signal that microglia use to communicate with neurons.

Koliwad says he believes these cells are altered when an individual is placed in an environment that’s obesogenic. “In the context of that,” he adds, “these microglia receive information from that environment milieu and transmit that information to the neurons that normally regulate body weight.”

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