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Omega-3s in fish oil - how they fight diabetes, inflammation

Posted Sep 04 2010 12:00am - The mystery of how the omega-3s in fish oil - EPA and DHA - relieve inflammation and improve insulin sensitivity has been discovered by researchers at the University of California, San Diego School of Medicine. The scientists have identified the molecular mechanism that makes omega-3 fatty acids so effective against chronic inflammation and insulin resistance.

The discovery - which centers on the so-called GPR120 receptor - could lead to development of a simple dietary remedy for many of the more than 23 million Americans suffering from diabetes and other conditions.  There are all sorts of ways to trigger inflammation; however, activation of GPR120 by omega-3s blocks not one, but all inflammatory pathways.

Writing in the advance online edition of the September 3, 2010 issue of the journal Cell, Jerrold Olefsky, MD, and colleagues identified a key receptor on macrophages abundantly found in obese body fat. Obesity and diabetes are closely correlated. The scientists say omega-3 fatty acids activate this macrophage receptor, resulting in broad anti-inflammatory effects and improved systemic insulin sensitivity.

Macrophages are specialized white blood cells that engulf and digest cellular debris and pathogens. Part of this immune system response involves the macrophages secreting cytokines and other proteins that cause inflammation, a method for destroying cells and objects perceived to be harmful. Obese fat tissue contains lots of these macrophages producing lots of cytokines. The result can be chronic inflammation and rising insulin resistance in neighboring cells over-exposed to cytokines. Insulin resistance is the physical condition in which the natural hormone insulin becomes less effective at regulating blood sugar levels in the body, leading to myriad and often severe health problems, most notably type 2 diabetes mellitus.

Olefsky and colleagues looked at cellular receptors known to respond to fatty acids. They eventually narrowed their focus to a G-protein receptor called GPR120, one of a family of signaling molecules involved in numerous cellular functions. The GPR120 receptor is found only on pro-inflammatory macrophages in mature fat cells. When the receptor is turned off, the macrophage produces inflammatory effects. But exposed to omega-3 fatty acids, specifically docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), the GPR120 receptor is activated and generates a strong anti-inflammatory effect.

“It’s just an incredibly potent effect,” said Olefsky, a professor of medicine and associate dean of scientific affairs for the UC San Diego School of Medicine. “The omega-3 fatty acids switch on the receptor, killing the inflammatory response.” The omega-3 treatment was as effective, or even more effective, than the popular insulin-sensitizing drug Rosiglitazone (trade name Avandia).

The NIH-supported scientists conducted their research using cell cultures and mice, some of the latter genetically modified to lack the GPR120 receptor. All of the mice were fed a high-fat diet with or without omega-3 fatty acid supplementation. The supplementation treatment inhibited inflammation and enhanced insulin sensitivity in ordinary obese mice, but had no effect in GPR120 knockout mice. A chemical agonist of omega-3 fatty acids produced similar results.

“This is nature at work,” said Olefsky. “The receptor evolved to respond to a natural product – omega-3 fatty acids – so that the inflammatory process can be controlled. Our work shows how fish oils safely do this, and suggests a possible way to treating the serious problems of inflammation in obesity and in conditions like diabetes, cancer and cardiovascular disease through simple dietary supplementation.”

What any of this means for humans isn’t yet clear, but a large number of people are already supplementing their diets with fish oil and an omega-3 prescription drug is already on the market for some indications. Olefsky isn’t going to make any recommendation at this point, but says he doesn’t see much of a downside to taking the supplements “as long as it isn’t in enormous doses.”

However, Olefsky said more research is required. For example, it remains unclear how much fish oil constitutes a safe, effective dose. High consumption of fish oil has been linked to increased risk of bleeding and stroke in some people.

Should fish oils prove impractical as a therapeutic agent, Olefsky said the identification of the GPR120 receptor means researchers can work toward developing an alternative drug that mimics the actions of DHA and EPA and provides the same anti-inflammatory effects.

The full text article is available free from this page:

Reference: Oh, Da Young, et al. GPR120 Is an Omega-3 Fatty Acid Receptor Mediating Potent Anti-inflammatory and Insulin-Sensitizing Effects. Cell, Volume 142, Issue 5, 687-698, 3 September 2010. doi:10.1016/j.cell.2010.07.041

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