SAN DIEGO— Researchers at the University of California San Diego School of Medicine have discovered the differential health effects of saturated and unsaturated fatty acids, according to a new paper published in the journal Cell. The findings also provide improved tools and a framework to once day treat obesity.
The researchers observed saturated fatty acids, such as palmitic acid, are potent activators of Jun kinases (JNK), key regulatory molecules implicated in the development of type 2 diabetes, insulin resistance, obesity and atherosclerosis. However, unsaturated fatty acids such as palmitoleic acid (POA) and eicosapentaenoic acid (EPA) not only do not activate JNK, but actually block JNK activation by palmitic acid.
Palmitic acid and POA differ in molecular structure by the presence of a single unsaturated bond (the absence of two hydrogen atoms) in POA. Cellular membrane fluidity is decreased upon incorporation of saturated fatty acids, which possess rigid hydrocarbon tails, but increased by the incorporation of unsaturated fatty acids with “bent" hydrocarbon tails.
The researchers searched for membrane-associated protein kinases that could account for the differential effects on JNK activity. They identified c-Src, a membrane-associated tyrosine kinase, as the molecule responsible for activation of JNK by palmitic acid and other saturated fatty acids. They also discovered that saturated fatty acids push c-Src into membrane subdomains of reduced fluidity and increased rigidity, where it accumulates in an activated form that eventually leads to JNK activation.
By contrast, POA and EPA prevent these changes in the membrane distribution of c-Src and—by blocking c-Src aggregation—they inhibit its activation by saturated fatty acids.
Most of the research was conducted using cultured cells (fibroblasts) treated with individual or combined fatty acids; however, the researchers also fed mice a high-fat diet (in which 60% of the calories were fat-derived) and reported similar c-Src accumulation within membrane subdomains of increased rigidity and JNK activation.
Currently, polyunsaturated fatty acids, such as EPA and structurally-related omega-3 fatty acids are used in the treatment of high cholesterol levels and may be effective in the treatment or prevention of type 2 diabetes. The researchers said understanding how EPA works could lead to the identification of even more potent EPA-like molecules.
