New research suggests that microglia, which are brain-resident immune cells, may offer a new target for obesity treatments. In mice, the scientists found that fat-rich diets cause microglia to trigger overeating and weight gain.
A paper on the work – led by the University of California-San Francisco (UCSF) and the University of Washington Medical Center in Seattle – is published in the journal Cell Metabolism.
The researchers believe that the discovery may lead to new obesity drugs that avoid many of the side effects associated with those currently approved for clinical use.
Co-senior author Suneil Koliwad, an assistant professor of medicine at the UCSF Diabetes Center, says that their findings suggest that microglia might be “an untapped and completely novel way to target the brain in order to potentially mitigate obesity and its health consequences.”
Microglia account for 10 to 15 percent of the cells in the brain and spinal cord. They are not the same as neurons, which are brain cells that communicate with each other using electrical and chemical signals.
Scientists are beginning to discover that these cells are highly active, even in the resting healthy brain. They are in constant motion, carrying out surveillance and triggering a wide range of responses.
It is coming to light that microglia also influence brain circuit activity during normal conditions. For example, during brain development, they help to shape brain circuits that are important for behavior and response to disease. In the mature brain, they can influence the activity of neurons.
It was already known that a group of neurons in the mediobasal hypothalamus help to regulate the amount of food we eat and how much energy we use.
Under normal conditions, this portion of the brain tries to balance our energy needs with the amount of calories we ingest from food and keep our weight healthy. However, researchers have discovered that eating fat-rich foods can disrupt this balancing process.
Previous research has shown that mice fed fat-rich diets eat more, burn fewer calories, and put on more weight than equivalent mice fed low-fat diets. Fat-rich diets also increase the number of microglia and inflammation in the mice’s mediobasal hypothalamus.
Prof. Koliwad and colleagues wanted to find out whether it is the increase in microglia that causes the overeating and weight gain, or whether it is the weight gain that increases the number of microglia.
The researchers ran an experiment wherein they put two groups of mice on a fast-food, fat-rich diet for 4 weeks. At the same time, one group of mice was treated with a drug that reduced the microglia in their mediobasal hypothalamus, while the other was not.
The results showed that the mice treated with microglia-reducing drug ate 15 percent less food and put on 20 percent less weight than the untreated group fed the same fatty diet.
This suggested that it was the increase in microglia that caused overeating and weight gain. However, it was still not clear whether or not this was due to the microglia triggering inflammation. Thus, the researchers conducted further experiments to find out.
They genetically engineered mice so that their microglia could not trigger immune responses. When fed the fatty diet, these mice ate 15 percent less food and gained 40 percent less weight than normal mice. This suggested that it was the ability of the microglia to trigger inflammation that caused it.
The researchers confirmed this in another group of mice that had been genetically engineered so that their microglia triggered inflammation in response to a drug.
They found that even when these mice were fed a healthful, low-fat diet, giving them the drug triggered their microglia to induce inflammation in the hypothalamus. This caused the treated mice to eat 33 percent more food, use 12 percent less energy, and put on four times more weight than untreated mice on the same diet.
The authors note that a drug currently undergoing human trials for the treatment of leukemia, other cancers, and arthritis acts in the same way as the drug that they used to reduce microglia in the mice. They are watching with interest to see if the drug causes the patients in the trials to lose weight.
The team also discovered that when the mice were fed the fat-rich diet, their microglia recruited extra immune cells from the bloodstream.
These blood-borne immune cells not only joined their cousins in the hypothalamus, but they also underwent changes that made them act in a similar way, increasing their inflammation response as well as their influence on energy balance.
The researchers say this suggests that there might be more than one way to influence the microglia to prevent weight gain: through one target in the brain and another target in the bloodstream.
Recent imaging studies show that, compared with slim people, obese people are more likely to have increased numbers of glial cells – the class that microglia belong to – in their hypothalamus. This localized increase of glial cells, called gliosis, is often seen in brain trauma, brain infection, brain cancer, and neurodegenerative diseases.
Speculating on why glia and microglia might behave in this way, Prof. Koliwad says that the answer might lie in evolution. Perhaps the response is an ancient survival mechanism that was effective in an era wherein energy-rich food was scarce, ensuring that people stored up reserves for leaner times by increasing their appetite.
“Microglial responsiveness to dietary fats makes some sense from this evolutionary perspective. Fats are the densest form of calories that ancient humans might ever [have] had the opportunity to consume,” he explains.
But in today’s modern world, in which high-fat foods are constantly available, the ancient survival advantage has become a disadvantage that can harm rather than preserve life.
Modern humans are more likely to overeat high-fat foods all the time, rather than once in a while. This causes the microglia trigger to be permanently on, leading to increased appetite and a vicious cycle of increasing intake of high-fat food.
The team now plans to investigate in more detail the mechanism through which eating fat-rich foods activates the microglia.
“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.”
Co-senior author Prof. Joshua Thaler, University of Washington Medical Center