How does the gut's immune system influence weight loss?
The finding may help explain why some people remain slim despite having eating habits that cause others to gain weight.
The mechanism works when intraepithelial T cells, which are a type of immune cell that resides in the lining of the small intestine, have an active gene for the protein integrin beta 7.
In a study paper on their work that now appears in the journal Nature, researchers at Massachusetts General Hospital and Harvard Medical School, both in Boston, MA, describe mice that do not have these particular cells as "metabolically hyperactive."
When they put mice lacking the cells on a high-fat, high-sugar diet, the animals did not develop obesity, high blood pressure, high cholesterol, heart disease, or diabetes.
"After you eat," says senior study author Filip K. Swirski, Ph.D., an associate professor of radiology who also works in the Center for Systems Biology, "your body can convert energy into heat and burn it quickly or it can convert the food into fat and store it for later use."
"These cells, which are known for their function in the immune system, also appear to play an important role in that metabolic choice," he adds.
Metabolism, fat storage, and energy use
The biochemistry of how the body handles nutrients derived from food digestion is complex and requires precise regulation.
The authors refer to "strategically positioned metabolic sensors" that direct nutrients down particular molecular pathways.
Their study identifies a pathway that prioritizes fat storage over energy use. Such a function can preserve health by ensuring that energy reserves are available during times of food scarcity.
However, for the many people who today live in societies with an abundance of high-fat, high-sugar foods, such a function is more likely to undermine health than support it.
Effect on metabolic syndrome
In the first part of the study, the team fed two groups of mice a normal diet. One group of mice (the controls) carried the gene for integrin beta 7, and their immune cells could therefore make the protein. The other group did not have the gene and therefore lacked the protein.
Although the mice lacking integrin beta 7 ate more than those with the protein and were equally as active, they did not put on more weight.
When they ran metabolic tests on the mice, the researchers found that those without integrin beta 7 had used more food for energy, suggesting that their "basal metabolism" worked at a higher rate than the control mice with the protein.
In addition, the mice lacking integrin beta 7 had better glucose and fat tolerance, had lower levels of triglycerides, and converted more glucose in brown fat into energy.
In the next part of the study, the team investigated the effect of a high-fat, high-sugar, and high-sodium diet on the two types of mice. Such a diet can trigger metabolic syndrome, which is a cluster of symptoms that raises the risk of type 2 diabetes and cardiovascular conditions.
On this diet, the control mice — that is, those with integrin beta 7 — developed obesity and other symptoms that characterize metabolic syndrome. Namely, they became glucose-intolerant and developed high blood pressure.
The mice lacking the protein, on the other hand, stayed slim and did not develop these other symptoms.
Effect on lipid levels
The researchers also tested the effect of silencing the gene for integrin beta 7 in the immune cells of mice predisposed to develop high cholesterol, which is another symptom of metabolic syndrome.
The team had induced predisposition to high cholesterol by genetically altering the mice and by feeding them a high-cholesterol diet.
The results showed that despite having the odds stacked against them in this way, the mice did not develop high cholesterol; their lipid levels stayed normal.
In addition, compared with counterparts with normal production of the protein in their immune cells, the mice lacking integrin beta 7 "excreted more cholesterol," showed better tolerance for glucose, and developed fewer cardiovascular risk factors, such as fewer plaques in their arteries.
Inhibits insulin release pathway
In a final part of the study, the researchers identified intraepithelial T cells as having the highest level of integrin beta 7.
They revealed that the cells exert their effect on metabolism by reducing the amount of GLP-1, a protein that normally promotes metabolism by triggering the release of insulin and the use of glucose.
There is still a lot of work to do to find out whether blocking these cells in humans could form the basis of new treatments for obesity, diabetes, and cardiovascular diseases.
Among the issues that require further investigation is exactly how the mechanism works in people that appear to have high rates of metabolism.
For instance, does it fluctuate during the day? And how does it change over a person's lifetime?
"We often speak of people who have a 'high metabolism' and seem to be able to eat whatever they want without gaining weight, while others struggle with obesity."
Filip K. Swirski, Ph.D.