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Obesity protection

iNKT cells ‘protect’ against obesity

Study provides insights in to the role of inflammation in metabolic disease
Lydia Lynch and Mark Exley (Courtesy Beth Israel Deaconess)

Researchers at Beth Israel Deaconess Medical Center (BIDMC) have found that Invariant natural killer T-cells (iNKT) play a protective role in guarding against obesity and metabolic syndrome.

NKT cells are a unique subset of immune cells that are known to influence inflammatory responses. They had been thought to be rare in humans.

However, Dr Lydia Lynch, a research fellow in the Department of Hematology/Oncology at BIDMC and the study’s first author, found they were plentiful in human adipose tissue.

“Our previous work had revealed a large population of iNKT cells in fat tissue in both mice and humans,” said Lynch. “Now we have identified them in mice and identified a role for them in the regulation of body weight and the metabolic state, likely by regulating inflammation in adipose tissue.”

Published on-line in the journal Immunity, the study also found that although iNKT cells are lost when humans become obese, they can be restored through weight loss. This suggests that therapies that activate iNKT cells could help manage obesity, diabetes and metabolic disease.

Research

Together with senior author Dr Mark Exley, assistant professor of medicine at Harvard Medical School, the team also discovered that a lipid called alpha-galactosylceramide (aGC) can lead to a dramatic improvement in metabolism, weight loss, fatty liver disease and can reverse diabetes by bolstering cells that have been depleted.

“We knew that not only did obese patients have more heart attacks and a greater incidence of Type 2 diabetes than lean individuals, but they also developed more infections than non-obese individuals,” she said.

Blood samples taken from these patients revealed that both NKT cells and iNKT cells were decreased, and subsequent studies of fat tissue from a group of obese patients who had lost weight following bariatric surgery showed that iNKT cells had increased to normal levels.

This data identified candidates for a protective role against the previous findings that adiposity due to diet (and negative energy expenditure) is the trigger for increased inflammation of fat tissue, which subsequently leads to insulin resistance and metabolic disorder.

“In obesity, excess lipids lead to larger, stressed fat cells that produce proinflammatory adipokines and cytokines, proteins that trigger an immune response and lead to insulin resistance,” said Lynch.

In this study, Lynch and colleagues conducted a series of animal experiments to test their hypothesis that iNKT cells play a physiological role in fat tissue regulation, and thereby protect against the development of inflammation and the metabolic syndrome.

Knowing that mice have iNKT cells in their liver tissue, the authors first ascertained that, like humans, the animals also harboured these cells in fat tissue.

After identifying larger number of cells, the research team proceeded to put the mice on a high-fat diet (60% calories from fat) and studied the outcomes.

“Similar to the human subjects we had previously studied, the animals lost their iNKT cells when they became obese,” she added. “Once we took them off this diet and put them back on a normal standard-fat diet, they lost the weight, and their iNKT cells increased.”

To better understand the exact role of the iNKT cells, the investigators examined two strains of knockout mice, the CD1d-/- and the Ja18-/-, both of which are deficient in iNKT cells.

“We put these knockout mice, and a group of control animals, on high-fat diets,” said Lynch. “While all of the animals grew obese, the response in the knockout mice was much more severe in that they grew 30% fatter than the control animals and developed the mouse equivalent of Type 2 diabetes very quickly, over just six weeks.”

The mice also had greatly increased triglyceride levels, larger adipocytes and fatty liver disease.

iNKT cells were then removed from a normal mouse and injected into obese NKT knockout mice.

They report that this actually reversed the diabetes and even though the mice continued to eat a high-fat diet, they lost one to two grams of weight  and exhibited a host of features that suggested reduced inflammation, including improved insulin sensitivity, lower triglycerides and leptin, and shrunken adipocytes.

aGC, a lipid known to activate iNKT cells, was then administered to see if the remaining diminished pool of iNKT cells in obesity could be activated to improve metabolism.

Using a single dose of aGC caused a dramatic improvement in metabolism and fatty liver disease, loss of much of the weight gained, and reversal of diabetes in the obese animals.

Implications

“aGC has been tested in clinical trials for the treatment of certain cancers, including melanoma and proven safe and produced few side effects in humans,” said Exley. “The effect of NKT stimulation, whether by aGC or other means, on weight loss, obesity and metabolic disorder has not been investigated until now and may provide a new avenue for the treatment of obesity and metabolic syndrome, which have now reached epidemic proportions worldwide.”

In addition to Lynch and Exley, study co-authors include BIDMC investigators Steven Balk, Michael Nowak, Bindu Varghese, Justice Clark and Vasillis Toxavidis; Andrew Hogan and Donal O’Shea of St. Vincent’s University Hospital, Dublin, Ireland; and Cliona O’Farrelly of Trinity College, Dublin, Ireland.

This study was supported by grants from the National Institutes of Health, the US Department of Defense, the UNESCO L’Oreal Fellowship; the European Commission Marie Curie Fellowship; the Science Foundation Ireland; and the Health Research Board, Ireland.

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