It's not just a high-fat diet that makes mice plumper than usual; a tweak to their immune system can also tilt the scales toward obesity.

It's not just a high-fat diet that makes mice plumper than usual; a tweak to their immune system can also tilt the scales toward obesity.

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Some obesity may be caused by a faulty immune system

Immune cells are usually described as soldiers fighting invading viruses and bacteria. But they may also be waging another battle: the war against fat. When mice lack a specific type of immune cell, researchers have discovered, they become obese and show signs of high blood pressure, high cholesterol, and diabetes. The findings have yet to be replicated in humans, but they are already helping scientists understand the triggers of metabolic syndrome, a cluster of conditions associated with obesity.

The new study “definitely moves the field forward,” says immunologist Vishwa Deep Dixit of the Yale School of Medicine, who was not involved in the work. “The data seem really solid.”

Scientists already know that there is a correlation between inflammation—a heightened immune response—and obesity. But because fat cells themselves can produce inflammatory molecules, distinguishing whether the inflammation causes weight gain or is just a side effect has been tricky.

When he stumbled on this new cellular link between obesity and the immune system, immunologist Yair Reisner of the Weizmann Institute of Science in Rehovot, Israel, was studying something completely different: autoimmune diseases. An immune molecule called perforin had already been shown to kill diseased cells by boring a hole in their outer membrane. Reisner’s group suspected that dendritic cells containing perforin might also be destroying the body’s own cells in some autoimmune diseases. To test the idea, Reisner and his colleagues engineered mice to lack perforin-wielding dendritic cells, and then waited to see whether they developed any autoimmune conditions.

“We were looking for conventional autoimmune diseases,” Reisner says. “Quite surprisingly, we found that the mice gained weight and developed metabolic syndrome.”

Mice lacking the dendritic cells with perforin had high levels of cholesterol, early signs of insulin resistance, and molecular markers in their bloodstreams associated with heart disease and high blood pressure. And a look at the immune systems of the mice revealed that they also had a different balance of T cells—a type of white blood cell that directs immune responses—than normal, Reisner and his colleagues report online today in Immunity. When the researchers removed these T cells from the mice, however, the lack of the dendritic cells no longer caused the animals to become obese or develop metabolic syndrome.

The results, Reisner says, suggest that the normal role of the perforin-positive dendritic cells is to keep certain populations of T cells under control. Just as perforin acts to kill cells infected with viruses, it can be directed to kill subsets of unnecessary T cells, he thinks. When the brakes are taken off those T cells, they cause inflammation in fat cells, which leads to altered metabolism and weight gain.

“We are now working in human cells to see if there is something similar going on there,” Reisner says. “I think this is the beginning of a new focus on a new regulatory cell.” If the results hold true in humans, he says, he could point toward a way to use the immune system to treat obesity and metabolic disease.

Daniel Winer, an endocrine pathologist at the University of Toronto in Canada and the lead author of a January Diabetes paper linking perforin to insulin resistance, says the new results overlap with his study. His group had found that mice lacking perforin—throughout their whole immune system, not just in dendritic cells—and fed a high-fat diet developed the early stages of diabetes. The new paper builds on that by homing in on perforin-positive dendritic cells and showing the link even in the absence of a high-fat diet. “It provides further evidence that the immune system has an important role in the regulation of both obesity and insulin resistance.”

Even if the results hold true in humans, however, the research is still far from leading to treatments for obesity or metabolic disease, Dixit says. “Talking about therapeutics at this point would be a bit of a stretch.” After all, injecting perforin into the body could kill cells beyond the T cell ones promoting obesity, he points out. Moreover, we can’t live without any T cells at all—they are vital for immunity against disease. But research on what the T cells are recognizing when they seek out fat cells and cause inflammation in fat tissue could eventually reveal drug targets. 

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