A TRINITY COLLEGE Dublin scientist, Marie Curie Fellow Lydia Lynch, has made a discovery about the role immune cells play in obesity and diabetes.
Her research is on immune cells known to be protective against malignancy, which are called invariant natural killer T-cells (iNKT), that are lost when humans become obese, but can be restored through weight loss.
The results of her studies have been published online this week in the journal Immunity, with Dr Lynch as first author in collaboration with colleagues at Harvard-affiliated Beth Israel Deaconess Medical Centre, and St Vincent’s University Hospital.
iNKT cells
iNKT cells had been thought to be rare in humans until work by Dr Lydia Lynch at Trinity College Dublin, Consultant Endocrinologist at St Vincent’s University Hospital Professor Donal O’Shea, and Trinity’s Professor of Comparative Immunology, Cliona O’Farrelly, found they were plentiful in human omental fat.
They then found a large population of iNKT cells in fat tissue from mice.
Dr Lynch’s Marie Curie Fellowship gave her the opportunity to work with Mark Exley and Steve Balk, who are both assistant professors of medicine at Harvard Medical School (HMS) and leaders in the field of natural killer T-cell (NKT) investigations.
Investigations
Dr Lynch first began this line of investigation in 2007. This was when her work with Professor O’Shea in the Obesity Clinic at St Vincent’s University Hospital in Dublin focused on the immune systems of obese patients.
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.
Blood samples taken from these patients revealed that both NKT cells and iNKT cells were decreased.
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.
Experiments
The new research was conducted with colleagues at BIDMC, St Vincent’s University Hospital, and Trinity College Dublin as animal experiments.
The authors used these to test their hypothesis that iNKT cells play a role in fat tissue regulation and protect against the development of inflammation and the metabolic syndrome.
The group needed to ascertain that, like humans, mice harboured these cells in fat .
Dr Lynch said the found “loads” of the cells. The research team then put the mice on a high-fat diet and studied the outcome.
Similar to the human subjects we had previously studied, the animals lost their iNKT cells when they became obese. 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.
In the next experiment, the authors examined two strains of mice, both of which are deficient in iNKT cells, and a group of control mice, all on a high-fat diet.
All the animals grew obese, but the iNKT-deficient mice grew 30 percent fatter than the control animals. They also developed the mouse equivalent of type 2 diabetes over just six weeks as well as greatly increased triglyceride levels, larger fat cells, and fatty liver disease.
For their next step, they removed iNKT cells from a normal mouse and injected them into obese NKT-deficient mice, explained Dr Lynch:
We actually reversed the diabetes, and even though the mice continued to eat a high-fat diet, they lost one to two grams of weight [normal mouse weight being 20 to 25 grams] and exhibited a host of features that suggested reduced inflammation, including improved insulin sensitivity, lower triglycerides and leptin, and shrunken adipocytes.
Metabolism
The final step was to demonstrate if the remaining pool of iNKT cells in obesity could be activated to improve metabolism.
The scientists tested aGC, a lipid known to activate iNKT cells and found that administering a single dose of aGC caused a “dramatic improvement” in metabolism and fatty liver disease. It also led to the loss of much of the weight gained, and reversal of diabetes in the obese animals.
Exley said that 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.
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.
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