Immune cells in 'love handles' could provide immunity against obesity
A Marie Curie research Fellow has uncovered a potential ally in the fight against obesity, together with a team of international researchers. The ally, found in our 'love handles', is a type of anti-tumour immune cell which protects against obesity and the metabolic syndrome that leads to diabetes.
Their results indicate that the invariant natural killer T-cells (iNKT) - which are vital for immunity - are lost when humans become obese, but can be restored through weight loss. As a result of their discovery they were able to show that therapies that activate iNKT cells could help manage obesity, diabetes and metabolic disease. Their results were published in the journal Immunity.
Obesity is a growing concern in the European Union. Statistics show that 10-30 % of adults are affected by obesity while 30-70 % are overweight. Meanwhile, the number of overweight babies and children in the World Health Organization (WHO) European Region rose steadily from 1990 to 2008; 60 % of children who are overweight before puberty will be overweight in early adulthood.
Childhood obesity has been associated with health risk factors for cardiovascular disease, type 2 diabetes, orthopaedic problems, mental disorders, underachievement in school and lower self-esteem. Statistics like these highlight the importance of research into ways of combating obesity.
As a result of research conducted by Marie Curie Fellow 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, iNKT cells have been discovered in human omental fat, which up until now had been considered rare in humans. Omental fat is the layer of tissue that lies underneath the muscles in the stomach - commonly referred to as the beer gut or love handles.
'We then found a large population of iNKT cells in fat tissue from mice,' said Dr Lynch, whose Marie Curie Fellowship gave her the opportunity to work with assistant professors of medicine at Harvard Medical School (HMS) and leaders in the field of NKT investigations. 'Now we have identified a role for these cells in the regulation of body weight and the metabolic state, likely by regulating inflammation in adipose tissue.'
This was not their only discovery. They also found that a lipid called alpha-galactosylceramide (aGC) can lead to a dramatic improvement in metabolism, weight loss and fatty liver disease, as well as reversing diabetes by bolstering cells that have been depleted.
Dr Lynch has been following this line of research since 2007 when she worked with Professor Donal O'Shea in the Obesity Clinic at St Vincent's University Hospital in Dublin, focusing 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,' she said.
Analysis done on blood samples from 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.
Based on what was already known, Dr Lynch and her colleagues at BIDMC, St Vincent's University Hospital and Trinity College Dublin conducted a series of animal experiments 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.
Large numbers of iNKT cells had been described in human and mouse liver tissue by Professors Mark Exley and Cliona O'Farrelly. Dr Lynch's group needed to ascertain that, like humans, mice also harboured these cells in fat, which is exactly what they found.
'We found loads of them,' Dr Lynch said.
Having found what they were looking for, the team then placed 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,' Lynch commented. '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.'
From this the authors then set out to better understand the precise role of the iNKT cells by examining two strains of mice, both of which are deficient in iNKT cells, and a group of control mice, all on a high-fat diet.
Although all the animals grew obese, the iNKT-deficient mice grew 30 percent fatter than the control animals and developed the mouse equivalent of type 2 diabetes over just six weeks. The mice also had greatly increased triglyceride levels, larger fat cells and fatty liver disease.
In the next step, the authors removed iNKT cells from a normal mouse and injected them into obese NKT-deficient mice.
'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,' Dr Lynch noted.
Finally, to see whether the remaining diminished pool of iNKT cells in obesity could be activated to improve metabolism, the scientists tested aGC, a lipid known to activate iNKT cells. They found that administering 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.
'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.'
- Project acronym: INKT CELLS
- Participants: Ireland
- Project FP7 255183
- Total costs: € 251 921
- EU contribution: € 251 921
Trinity College Dublin