Don't Always Blame Overeating For Weight Gain

Highlights

• Immune cells in the brain called microglia are triggered in response to diets rich in fat, causing weight gain.
• A fast food-like diet rich in fat for four weeks, activates local inflammation within the key groups of neurons that regulate food intake and energy expenditure.
• Multiplying microglia are a cause of overeating and obesity in these mice, rather than a result of their weight gain.

Microglia, the immune cells in the brain trigger overeating and weight gain in response to diets rich in fat, according to a new study in mice led by researchers from UC San Francisco and the University of Washington Medical Center. 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.

"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 diet.

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.

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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 high-fat diet, 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.

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"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.

Reference

1. Suneil Koliwad et al., Brain's immune cells may drive overeating and weight gain, Cell Metabolism (2017).

Source-Medindia