Maintaining body weight isn’t as simple as burning off all the calories eaten in a day. The brain plays an important role. It determines what you eat, how much and when. And the brain’s immune cells contribute, too, a new study in mice shows. Turning on these cells can make a fatty diet more fattening. Getting rid of those cells, known as microglia, can make the animals eat less and gain less weight.
These microglia can inflame a particular area of the brain. And in mice, this process could make the animals gain weight — even when they weren’t eating a fatty diet.
“I think it’s really neat,” says Kate Ellacott, who was not involved in the study. “This is the first time anyone’s shown if you change the way microglia can behave — if you make them more inflammatory — you can impact bodyweight.” Ellacott is a neuroscientist, someone who studies the brain, at the University of Exeter in England.
The immune system is a collection of cells that can move throughout the body to help fight infection and damage. When a part of the body is stressed or injured, the hurt part sends out chemical distress calls. Those messages are like an alarm. They tell immune cells where to swoop in so that they can destroy damaged cells or gobble up germs.
Along the way, immune cells cause inflammation. This response can include redness and swelling. People often think of inflammation as a swollen knee or the redness surrounding a cut. Here, Ellacott points out, the immune system works to “restore balance.” The immune system tries “to repair tissues and get back to normal,” she explains.
But sometimes, inflammation sticks around for the long term, even when it’s not supposed to. Such chronic inflammation does not have to include redness. But it will cause harm. “If you have a disease where inflammation never goes away, you can get damage to the tissue,” she points out.
One condition where chronic inflammation occurs is obesity. Eating a high-fat diet for a while makes animals gain weight and activates their immune cells, says Joshua Thaler. He’s an endocrinologist (someone who studies the hormones in the body) and a neuroscientist. He works at the University of Washington in Seattle. There, his team performed the new study.
The brain is full of cells called neurons. But they aren’t alone. A variety of other cell types live there too, Thaler notes. For a while, scientists thought some of these cells, called glia (GLEE-ah), were just there to support neurons and to hold them together. (In fact, “glia” comes from the Greek word for glue.) But glia are far more than just brain glue. Some of them, called microglia, act as an immune army in the brain. They move into injured areas and can turn on inflammation when things go wrong.
Thaler’s team already had found that one brain area gets inflamed when mice eat a high-fat diet. Called the hypothalamus, this brain area helps to regulate how much mice — and people — eat. They even showed similar changes in the brains of people with obesity.
Could the microglia in the hypothalamus be the reason why? To find out, Thaler and his colleagues fed high-fat diets to more mice. Then they gave some of these mice a drug that killed off microglia. Without these immune cells, those mice gained less weight and ate less food. But losing their microglia had no effect on mice dining on low-fat chow.
The researchers wanted to make sure microglia were causing the inflammation that led to weight gain. So they deleted a gene — a set of cellular instructions. Microglia use this gene to make their inflammatory signals. The treated mice gained less weight on a high-fat diet, just as in the mice with no microglia at all.
If stopping inflammatory signals made mice gain less weight, more inflammation might have the opposite effect. Thaler’s group decided to test that idea. They worked with mice that were unable to make an important inflammation-fighting molecule. These mice developed inflammation in their brains. They also gained weight — even when they weren’t on a high-fat diet! That confirmed that brain inflammation alone could contribute to obesity.
Thaler and his colleagues published their findings July 5 in the journal Cell Metabolism.
Calling in the immune cavalry
Microglia are full-time brain residents. “They’re always there,” Ellacott says. These cells move to wherever the brain needs them.
When mice eat a high-fat diet, the hypothalamus recruits microglia. And these immune cells then call for backup. In the new study, some of those backup immune cells had come from a mouse’s bone marrow.
Usually, immune cells in the marrow can’t reach the brain. There’s a barrier between the blood and the brain that stops them. That blood-brain barrier exists to keep potentially dangerous cells and other foreign substances from getting in.
Somehow, a high-fat diet let those marrow-based backup cells break into the brain.
Some scientists had seen immune cells getting into other organs after a high-fat diet, Thaler notes. But his group has now shown it also happens in the brain. “I was not a believer that the [immune cells] were going to come marching into the brain,” he recalls, so “it was a bit of a surprise.”
Scientists might someday be able to reduce inflammation by targeting the microglia, Ellacott says. If they can develop a drug that works this way in people, scientists might use it to treat all types of brain diseases linked with inflammation, not just obesity.
Microglia in the brain may contribute to weight gain, Thaler says. “But clearly they aren’t the whole story.” Turning off the microglia, or stopping them from sending inflammatory distress calls, causes mice to gain less weight. But in the end, those mice still became overweight. And while mice with brain inflammation gained weight on even a low-fat diet, he notes that they never got as fat as did the mice downing high-fat chow.
The brain’s immune system may be a part of the obesity story, Thaler says, “but there’s clearly more we need to learn.”
blood brain barrier A barrier of tightly packed cells that carefully regulate what molecules can — and can’t — enter the brain. The barrier protects the brain from foreign substances in the blood and helps to maintain a constant environment for brain cells.
cell The smallest structural and functional unit of an organism. Typically too small to see with the unaided eye, it consists of a watery fluid surrounded by a membrane or wall. Depending on their size, animals are made of anywhere from thousands to trillions of cells.
chemical A substance formed from two or more atoms that unite (bond) in a fixed proportion and structure. For example, water is a chemical made when two hydrogen atoms bond to one oxygen atom. Its chemical formula is H2O. Chemical also can be an adjective to describe properties of materials that are the result of various reactions between different compounds.
chemical signal A message made up of molecules that get sent from one place to another.
chronic A condition, such as an illness (or its symptoms, including pain), that lasts for a long time.
colleague Someone who works with another; a co-worker or team member.
diet The foods and liquids ingested by an animal to provide the nutrition it needs to grow and maintain health.
endocrinologist A doctor who specializes in conditions affecting the production of hormones or the body’s response to hormones.
fat A natural oily or greasy substance occurring in plants and in animal bodies, especially when deposited as a layer under the skin or around certain organs. Fat’s primary role is as an energy reserve. Fat also is a vital nutrient, though it can be harmful if consumed in excessive amounts.
gene (adj. genetic) A segment of DNA that codes, or holds instructions, for a cell’s production of a protein. Offspring inherit genes from their parents. Genes influence how an organism looks and behaves.
germ Any one-celled microorganism, such as a bacterium or fungal species, or a virus particle. Some germs cause disease. Others can promote the health of more complex organisms, including birds and mammals. The health effects of most germs, however, remain unknown.
glia Non-nerve cells that make up 85 percent of the brain’s cells. Some glial cells wrap around a nerve’s axon (it’s long shaft). This speeds the rate of neural signaling and helps prevent confusing “cross-talk” between neighboring nerve cells.
hormone (in zoology and medicine) A chemical produced in a gland and then carried in the bloodstream to another part of the body. Hormones control many important body activities, such as growth. Hormones act by triggering or regulating chemical reactions in the body.
hypothalamus A region of the brain that controls bodily functions by releasing hormones. The hypothalamus is involved in regulating appetite through release of appetite-suppressing hormones.
immune system The collection of cells and their responses that help the body fight off infections and deal with foreign substances that may provoke allergies.
infection A disease that can spread from one organism to another. It’s usually caused by some type of germ.
inflammation (adj. inflammatory) The body’s response to cellular injury and obesity; it often involves swelling, redness, heat and pain. It also is an underlying feature responsible for the development and aggravation of many diseases, especially heart disease and diabetes.
journal (in science) A publication in which scientists share their research findings with experts (and sometimes even the public).
marrow (in physiology and medicine) Spongy tissue that develops inside of bones. Most red blood cells, infection-fighting white blood cells and blood platelets form within the marrow.
metabolism The set of life-sustaining chemical reactions that take place inside cells and bigger structures, such as organs. These reactions enable organisms to grow, reproduce, move and otherwise respond to their environments.
microglia A type of cell found in the brain and spinal cord. It can move from place to place, and serve as part of the immune system, protecting the brain from infection.
molecule An electrically neutral group of atoms that represents the smallest possible amount of a chemical compound. Molecules can be made of single types of atoms or of different types. For example, the oxygen in the air is made of two oxygen atoms (O2), but water is made of two hydrogen atoms and one oxygen atom (H2O).
neuron An impulse-conducting cell. Such cells are found in the brain, spinal column and nervous system.
neuroscientist Someone who studies the structure or function of the brain and other parts of the nervous system.
obese Extremely overweight. Obesity is associated with a wide range of health problems, including type 2 diabetes and high blood pressure.
organ (in biology) Various parts of an organism that perform one or more particular functions. For instance, an ovary is an organ that makes eggs, the brain is an organ that makes sense of nerve signals and a plant’s roots are organs that take in nutrients and moisture.
regulate (n. regulation) To control with actions. Governments write rules and regulations — laws — that are enforced by police and the courts.
tissue Made of cells, any of the distinct types of materials that make up animals, plants or fungi. Cells within a tissue work as a unit to perform a particular function in living organisms. Different organs of the human body, for instance, often are made from many different types of tissues.
Journal: M. Valdearcos et al. Microglial inflammatory signaling orchestrates the hypothalamic immune response to dietary excess and mediates obesity susceptibility. Cell Metabolism. Published online July 5, 2017. doi: 10.1016/j.cmet.2017.05.015.