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Immune cells in the gut may determine whether our metabolisms run hot or cold, a new study suggests.
Experiments done in specially engineered mice found that certain immune cells in the small intestine tended to slow down metabolism and send ingested food to be stored as fat rather than converting it to energy, according to the study published Wednesday in Nature. Mice engineered to lack these immune cells could consume diets high in fat, sugar and salt without developing conditions such as obesity, diabetes, hypertension and heart disease, researchers reported.
The hope, experts say, is that these findings will suggest ways to tweak something in the guts of people genetically programmed to have "thrifty" or slow metabolisms. Perhaps by bumping up levels of certain substances in the gut, metabolisms can be revved up to run hotter, thus allowing people to eat a little more without gaining weight.
“When you eat a meal, your body needs to decide what to do with the energy in the meal,” said study coauthor Filip Swirski, an associate professor at the Harvard Medical School and a principle investigator at the Center for Systems Biology at the Massachusetts General Hospital. “The immune cells calibrate that decision and essentially they put the brakes on a high metabolism.”
Swirski and his colleagues started out by focusing on a protein, called integrin beta7, that directs immune cells to the gut. Mice without the gene for the protein ate a lot more than those with it, but didn’t gain weight, despite being no more active than the normal mice.
“They just run hot,” Swirski said. “They have a higher basal temperature.”
The researchers next tried feeding both groups of mice food that was high in fat, sugar and sodium, the kind of diet known to induce metabolic syndrome — a constellation of symptoms, including high blood pressure, sugar and cholesterol, associated with a higher risk of heart disease.
The mice without beta7 stayed trim and did not develop glucose intolerance, which leads to higher than normal levels of blood sugar and high blood pressure.
In contrast, the normal mice became obese and developed high blood pressure and reduced glucose tolerance.
The researchers next looked at the impact of this protein on mice that were vulnerable to developing high cholesterol and hardening of the arteries. Once again, mice that were missing the beta7 protein were healthier, maintaining normal fat levels, despite being fed a diet high in cholesterol.
But how was beta7 affecting metabolism?
To answer that question Swirski and his colleagues focused on certain immune cells known as T-cells, in the small intestine.
“This is where we stumbled on GLP-1,” a metabolism-stimulating protein, Swirski said.
Swirski and his colleagues discovered that the T cells they had been studying had abundant GLP-1 receptors. The mice with more beta7, but not GLP-1 receptors, had faster metabolisms. That proved “the crucial cells were T cells that express the GLP-1 receptor,” Swirski said.
Slow metabolism helped survival
Now that the researchers had found the metabolism-slowing cells, Swirski started to wonder why mice — and humans — would have a system that slowed the metabolism down.
One possible reason is how humans evolved to survive food shortages over millions of years. “Having this kind of brakes under those conditions would be advantageous to survival,” Swirski said. “It would mean you could store ingested food for longer since it was converted to fat to be used if you didn’t have frequent meals.”
That’s only become a problem in recent times. “When there is so much over-nutrition, the system backfires,” Swirski said.
The new research may have major significance for humans, said UCLA gastroenterologist Dr. Emeran Mayer, author of “The Mind-Gut Connection: How the Hidden Conversation Within Our Bodies Impacts Our Mood, Our Choices, and Our Overall Health.”
The researchers have shown that the immune cells in the gut “regulate metabolism, contributing to the development of obesity, metabolic syndrome and cardiovascular disease in the presence of a high-fat, high-sugar diet,” Emeran said in an email.
Why some don't gain weight
Calling the new research “provocative,” Dr. Toren Finkel said it might help scientists find new ways to help people battling weight gain. There have long been hints of a connection between the immune system and obesity, said Finkel, director of the Aging Institute at the University of Pittsburgh Medical Center.
“The inflammatory response to obesity drives a lot of the problems associated with it.”
Intriguingly, there are already diabetes drugs out there that mimic GLP-1, Finkel noted.
This new insight into the biology of immune cells and metabolism “is extremely important,” said Dr. Michael Blaha, director of clinical research at the Ciccarone Center for the Prevention of Heart Disease at Johns Hopkins Medicine.
It suggests an explanation for why some people tend to be overweight and some are resistant to becoming overweight. “And it’s telling us that the story is way more complicated than a simple calculation of ‘calories in and calories out,’” he said.
“For a long time we’ve treated the consequences of obesity — such as high blood pressure and high cholesterol — because we have not had ways to attack the causes of obesity,” said Blaha. “It would be much better if we were able to treat the reasons for a disordered metabolism rather than its consequences.”