April 12, 2012

Study seeks clues to obesity-related inflammation

by Bill Snyder

Obesity is not only about fat. It occurs against a background of chronic, low-level inflammation that can trigger insulin resistance, type 2 diabetes and fatty liver disease.

Now researchers at Vanderbilt University have discovered that an unusual set of immune cells, called invariant natural killer T cells (iNKT cells), can fan the flames of obesity-related inflammation.

Their findings, reported in the current issue of the Proceedings of the National Academy of Sciences (PNAS), suggest that targeting these cells could lead to new ways to prevent metabolic disorders in obesity.

“Our findings have identified iNKT cells as new players in the complex network linking lipid accumulation to inflammation in obesity,” said first author Lan Wu, M.D., research assistant professor of Pathology, Microbiology & Immunology.

While conventional T cells are activated by protein fragments to attack invading pathogens, iNKT cells recognize fat molecules (lipids) and sugar-modified fat molecules (glycolipids). It’s this attraction to fat that brings iNKT cells into the obesity arena.

Invariant NKT cells normally regulate inflammatory responses by releasing a range of small proteins called “cytokines” that have both pro-inflammatory and anti-inflammatory effects.

In their studies in mice, the Vanderbilt researchers found that a high-fat diet promoted “hyperresponsiveness” in iNKT cells, leading to overproduction of pro-inflammatory cytokines, worsening tissue inflammation, insulin resistance and excessive accumulation of lipids by the liver.

This was not observed in mice that lacked iNKT cells. “The consistent results … point toward iNKT cells … as the main culprits,” the researchers concluded.

While the exact mechanism linking excess dietary lipid to iNKT cell activation is not yet known, “our findings suggest that selective depletion of iNKT cells with a … specific antibody might beneficial in protecting (people) from obesity-associated metabolic disease,” they write.

Wu’s colleagues included her husband, Luc Van Kaer, Ph.D., professor of Pathology, Microbiology and Immunology, and the paper’s senior author, and David Wasserman, Ph.D., director of the Vanderbilt Mouse Metabolic Phenotyping Center.

The study was supported by the American Diabetes Association, National Institutes of Health and the Vanderbilt Diabetes Research and Training Center.