Natural Killer T-Cells Prevent Obesity

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HeConnection-Treatment-Natural Killer T-Cells Prevent ObesityNatural Killer T-Cells Prevent Obesity – Invariant natural killer T-cells (iNKT) are a unique subset of immune cells that are known to influence inflammatory responses. Now, a scientific team led by researchers at Beth Israel Deaconess Medical Center (BIDMC) has found that iNKT cells play a protective role in guarding against obesity and the metabolic syndrome, a major consequence of obesity.

Their discovery, published in the journal Immunity, also finds that although iNKT cells are lost when humans become obese, they can be restored through weight loss, and further suggests that therapies that activate iNKT cells could help manage obesity, diabetes and metabolic disease.

iNKT cells had been thought to be rare in humans until work by Lydia Lynch, PhD, found they were plentiful in human adipose (fat) tissue.

“Our previous work had revealed a large population of iNKT cells in fat tissue in both mice and humans,” explains Lynch, a research fellow in the Department of Hematology/Oncology at BIDMC and the study’s first author. “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.” Together with senior author Mark Exley, PhD, Assistant Professor of Medicine at Harvard Medical School and a leader in the field of NKT investigations, 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.

Knowing that mice have iNKT cells in their liver tissue, the authors first ascertained that, like humans, the animals also harbored these cells in fat tissue. “We found loads of them,” says Lynch, explaining that the research team next proceeded to put the mice on a high-fat diet (60 percent calories from fat, typically lab-produced, saturated fatty acids) and studied the outcomes. “Similar to the human subjects we had previously studied, the animals lost their iNKT cells when they became obese,” explains Lynch. “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.”

The Role of iNKT Cells

In the next experiment, the authors set out to better understand the exact role of the iNKT cells by examining 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 [saturated] fat diets,” says Lynch. “While all of the animals grew obese, the response in the knockout mice was much more severe in that they grew 30 percent 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.

Next, the authors removed iNKT cells from a normal mouse and injected them into obese NKT knockout mice. “By doing this, 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.”

Finally, in order to demonstrate if the remaining diminished pool of iNKT cells in obesity could be activated to improve metabolism, the scientists tested alpha-galactosylceramide (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,” explains 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.”

Health-e-Solutions Comment

This sounds like promising research using a lipid (fat) that has already been proven to be safe for humans. However, it remains to be seen if it will be more effective and safe than changing diet and lifestyle to reduce weight and improve diabetes control. It appears that doing so can also increase iNKT cells. We think the Roman DIet and Health-e-Solutions lifestyle has helped our family lose excess weight and maintain normal body weight.

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