Fat fighter

CAN AN immune cell found in fat tissue and blood protect against obesity and its related ills? And could it even help to reverse them?

Those are the intriguing suggestions from a new study involving Irish researchers and patients.

The research found that both humans and mice lose a type of immune cell called an invariant natural killer T (iNKT) cell in obesity, but – in mice at least – bumping the cells back up again resulted in weight loss and better metabolic health, even though they continued to eat a high-fat diet.

The findings shed more light on the links between obesity and the immune system, explains researcher Dr Lydia Lynch, a Marie Curie research fellow at Harvard Medical School and Trinity College Dublin.

“Obesity and its related diseases threaten to shorten the lifespan by five to 20 years, and much of this is due to inflammation,” she explains. “Inflammation in fat – in other words when immune cells infiltrate fat and become active – is now known to play a major role in development of insulin resistance and diabetes, directly linking the immune system and obesity and metabolism.”

Lynch and her colleagues became interested in iNKT cells because they are sensitive to lipids. Until recently, these immune cells had been thought to be rare in humans, but Lynch found enriched populations of them in fat tissue in lean humans. And she saw that the numbers of iNKT cells seem to fall away in obesity.

The new study, published in Immunity, went further and worked out that when obese humans lost excess weight, their levels of iNKT cells went up. But humans aren’t always the most practical of models to study in the lab, so the researchers turned to mice.

The study found that the animals also have plenty of iNKT cells in their fat tissue, and again the numbers plummet in obesity, suggesting there are parallels between mouse and human when it comes to iNKT cells and fat. And their new experiments suggest that iNKT cells are not just passive bystanders in obesity and its fallout. Instead, they seem to be protective.

“We wondered what would happen if there were no iNKT cells and you became obese, so we looked to mice models that had no iNKT cells,” says Lynch. “When these iNKT-knockout mice ate a high-fat diet, they became fatter and developed insulin resistance, and they had more inflammation in their fat compared to normal mice eating a high-fat diet.”

And what really sealed the deal was that introducing iNKT cells to the obese mice seemed to transform them. “We then put iNKT cells back into these obese knockout mice and found that even though the mice still ate a high-fat diet, they lost weight and their diabetes went away,” says Lynch.

A similar thing happened when they gave obese mice a lipid called alpha-galactosylceramide (aGC), which activates iNKT cells – they lost weight and got healthier, despite the high-fat fare.

“The mice that received only one dose of aGC to activate their iNKT cells continued to eat and were not sick, but lost weight and their diabetes was greatly improved,” says Lynch, who points out that the compound has been used in humans before, but not for this purpose.

The human data in the new study came from patients attending the weight management clinic in St Columcille’s Hospital in Loughlinstown.

“Over 1,000 patients have now given blood samples to help the research,” says Prof Donal O’Shea, a consultant endocrinologist at St Columcille’s and St Vincent’s University Hospital who runs a weight management service for adults.

“The idea for this work came from their generosity and is opening up a new field in the area of obesity and diabetes research. It wouldn’t have happened without them.”

O’Shea is a co-author on the new study and he believes it will change the perception of obesity by highlighting how the body’s innate immune system could be making it harder for people who are obese to lose excess weight, in part because they lack iNKT cells.

“Obesity affects the immune system – we knew that alright – but the immune system affecting weight and obesity wasn’t on the agenda,” he says of the results they saw in mice. “It very soon made sense though.

“Weight loss is a huge threat to any living cell – and this work shows that the immune system is there to maintain weight. I think the long-term impact of the recognition that your innate or primal immune system is involved in regulating weight will change how we perceive the fight against obesity – and it certainly should drive the imperative for prevention. If your primal immune response is involved in defending against weight loss – that becomes a very tough battle.”

Prof O’Shea notes that both obesity and the immune system are complex, and it will be a while before we understand the interplay there. “Lydia’s work and the other work in the area puts the immune system firmly on the pitch as a player in how our weight is controlled,” he says. “It will be some time before we have the mechanisms worked out – and new therapeutic strategies arising from it.”