Researchers have new evidence to explain how saturated fatty acids, which soar in those who are obese, can lead the immune system to respond in ways that add up to chronic, low-grade inflammation. The new results could lead to treatments designed to curb that inflammatory state, and the insulin resistance and type 2 diabetes that come with it.
One key, according to the report in the November Cell Metabolism, a Cell Press publication, is an immune receptor (called Toll-like receptor 4 or Tlr4) at the surface of blood cells, including a particularly "angry" class of macrophages known to pump out toxic molecules and spur inflammation. It now appears that fatty acids may in essence "hijack" those immune cells via Tlr4.
"Tlr4 is out there to sense bacterial products, but one of those looks a lot like fatty acids," said the study's senior author Jerrold Olefsky of the University of California, San Diego. "They don't know it's not bacteria."
That bacterial product is something called lipopolysaccharide (LPS) found in bacterial membranes. Olefsky notes, however, that they have not yet fully demonstrated that fatty acids bind Tlr4 directly.
Scientists had suspected that Tlrs might be the "sensors" linking obesity to inflammation. Indeed, earlier studies had supported that notion. In the new study, the researchers show that this interaction is particularly important in the bloodstream. Mice lacking Tlr4 only in blood cells grew obese when they were fed a high-fat diet, but they were largely spared the metabolic consequences of their obesity. The mice were fat, but metabolically they continued to "look pretty normal," Olefsky said.
The researchers showed in another Cell Metabolism report last year that a "genetic trick" designed to kill off the offending macrophages, which are distinguished by a CD11c marker, could reverse insulin resistance in obese mice. The method used by the team wasn't one that they could consider translating into the clinic, however (http://www.eurekalert.org/pub_releases/2008-10/cp-ki093008.php).
The new findings suggest one that could. "A Tlr4 antagonist – now that's a therapeutic," Olefsky said. "The jury is still out, but it sure makes sense they could be a new class of insulin sensitizers."
They say that drugs aimed at Tlr4 have already been developed, and the idea that those drugs may hold promise in fighting insulin resistance and type 2 diabetes is one Olefsky's team is now exploring in detail in the mice.
The researchers include Maziyar Saberi, University of California, San Diego, La Jolla, CA; Niels-Bjarne Woods, The Salk Institute for Biological Studies, La Jolla, CA; Carl de Luca, University of California, San Diego, La Jolla, CA; Simon Schenk, University of California, San Diego, La Jolla, CA; Juu Chin Lu, University of California, San Diego, La Jolla, CA; Gautam Bandyopadhyay, University of California, San Diego, La Jolla, CA; Inder M. Verma, The Salk Institute for Biological Studies, La Jolla, CA; and Jerrold M. Olefsky, University of California, San Diego, La Jolla, CA.
Journal
Cell Metabolism