Some people just never gain excess weight no matter what they eat, a phenomenon many diet experts attribute to a healthy balance of eating and burning calories. But Massachusetts General Hospital (MGH) researchers believe a type of immune cell in the gut is key to controlling the body's metabolism and may be a therapeutic target for conditions such as obesity and heart disease.
The cells are called intraepithelial T lymphocytes, and they exist in the lining of the small intestine. To study them, the researchers started with a protein called integrin beta 7, which is known to direct immune cells to the gut. They observed that in mice that were lacking the gene that encodes the protein, more food was converted into energy instead of being stored as fat. The rodents also showed many other signs of higher metabolic activity: They burned more glucose in brown fat and were more glucose-tolerant. They also had lower triglyceride levels and better fat tolerance than did control mice.
The MGH scientists reported their findings in a study in the journal Nature.
“The [beta 7-negative] mice become metabolically hyperactive and, even when consuming a diet very high in fat and sugar, are able to resist metabolic diseases such as obesity, hypertension, hypercholesterolemia, diabetes, and atherosclerosis,” said senior author Filip Swirski, Ph.D., in a statement.
Intraepithelial T cells appear to regulate metabolism via GLP-1, which is known for its ability to increase insulin secretion and glucose uptake, the MGH researchers reported. In fact, GLP-1 and its receptor are already targeted in Type 2 diabetes therapies such as Novo Nordisk’s Victoza and Eli Lilly’s Trulicity. When intraepithelial T cells are present, GLP-1’s activity seems to be limited, leading to a metabolism slowdown and energy conservation in the form of fat accumulation, according to the MGH team.
Swirski speculated that humans might have developed that conservation mechanism during long periods when food was scarce. “Now with food so abundant, this energy-saving mechanism can backfire and lead to unhealthy outcomes,” he said.
Many researchers have looked to the gastrointestinal tract, where food is digested and absorbed, for clues to metabolic disorders. The gut microbiome is a popular target. A team at the University of Pennsylvania recently discovered that disruption of the biological clock and a previous history of obesity can change the gut microbiome in a way that makes people susceptible to obesity.
Findings by Swirski and colleagues shed new light on the link between “gut metabolic food sensors and cardiovascular disease, and might open new therapeutic avenues to treat patients with a host of related conditions,” said Michelle Olive, Ph.D., an official at the NIH’s National Heart, Lung, and Blood Institute, which funded the study.
Of course, some key questions still await answers, including the exact mechanism by which these cells affect GLP-1 and metabolism, and whether there are indeed fewer of them in people with a higher basal metabolism. Swirski added that more research needs to be done to figure out how to translate the finding into therapies to treat metabolic disorders.