Macrophages - the scavenger cells of the body's immune system - are known as troublemakers for the role they play in obesity, but Stanford University School of Medicine researchers have found that the cells can also be saviors when it comes to metabolism.
The researchers highlight the beneficial role of macrophages in combating the effects of a high-fat diet in mice in a study that will be published in the May 21 advance online edition of Nature. "Macrophages have a reputation for being the bad guys," said the study's senior author, assistant professor of medicine Ajay Chawla, MD, PhD. "We have found that they can also do good things."
Chawla and his colleagues have identified a molecular "switch" that can shift the cells into the more desirable mode, a finding that could play a role in blocking the development of insulin resistance and type-2 diabetes seen with obesity.
"We have identified a previously unappreciated role that the macrophage can play in protecting against the deleterious effects of a high-fat, or 'Western,' diet," said one of the article's lead authors, Justin Odegaard, an MD/PhD student in Chawla's lab. The deleterious effects include obesity and insulin resistance, which put a person at higher risk for heart disease and type-2 diabetes.
"These results are very exciting because they challenge the typical view in the field of obesity research where investigators tend to think of the macrophage as a pathogenic cell in Western diet-induced obesity and insulin resistance," said Roberto Ricardo, the other lead author, who is also an MD/PhD student in Chawla's lab.
Macrophages once seemed an unlikely participant in obesity. They are white blood cells that swallow and digest cellular debris and pathogens, triggering other immune cells to aid in the response to a pathogen. But in recent years, macrophages found in fat tissue of obese animals have been fingered as the source of chemical signals that exacerbate the problems of obesity and insulin resistance that accompany eating too much fat.
In this villainous role, activated macrophages release chemical signals that trigger inflammation. The increased blood flow of inflammation is necessary for wound healing and clearing infections, but long-term inflammation interferes with normal cellular processes and leads to many of the chronic conditions that plague modern society, including heart disease, obesity and type-2 diabetes.
Chawla's group investigated the opposite effect - the macrophage's resolution of inflammation. They wanted to figure out what flipped the cells into that mode, known as alternative activation.
The researchers reasoned that an impairment in alternative activation might be the cause of the prolonged inflammation and insulin resistance. They focused on a molecule found in the nucleus of cells called PPAR-gamma, which has been implicated in how cells detect fatty acids, the building blocks of dietary fat.
The researchers bred genetically engineered mice that did not have the PPAR-gamma molecule in their macrophages. It turned out that simply missing PPAR-gamma in macrophages caused mice to gain about 20 percent more weight than their normal counterparts, and predisposed them to the development of diet-induced insulin resistance. "We predicted that the inflammation might be higher and there might be insulin resistance, but it was a surprise that the mice actually gained weight," said Chawla.
What they found, he said, is that macrophages are lost in the case of excess fat consumption, and those lost are specifically the ones that undergo the alternative activation program. "When you lose these cells, the adipose tissue can't deal with incoming lipids properly, and the mice become fat as well as glucose intolerant and insulin resistant," said Chawla. "Basically when the system gets overwhelmed, the reparative responses get overwhelmed as well."
"These findings are especially exciting because other research has recently shown the same differences in macrophage activation in humans," said Odegaard. He added that the fat reserves of obese people have been found to contain inflammatory macrophages whereas those of lean people contain anti-inflammatory macrophages, replicating the observations made in their animal model. Prior research has also shown that when people lose a lot of weight, the profile of their macrophages changes, shifting to the anti-inflammatory mode.
Now that they have identified a molecular switch, the researchers are pursuing further studies to nail down the details of how the cells flip-flop between the two modes, with the hope that someday drugs might be able to promote macrophages into their alternative state. This work also raises the possibility that existing anti-inflammatory therapies might be targeted at adipose tissue macrophages to treat obesity and insulin resistance.
Other Stanford contributors to this study are: endocrinology research associates Matthew Goforth and Christine Morel; postdoctoral scholar Lata Mukundan, PhD; medical student Alex Red Eagle and postdoctoral scholar Divya Vats, MD. This work was supported by grants from the National Institutes of Health, Astellas Foundation, Takeda Pharmaceuticals North America, Rockefeller Brothers Fund, Goldman Philanthropic Partnerships, the Stanford Medical Scientist Training program, the American Heart Association and the Howard Hughes Medical Institute Gilliam Fellowship.
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