Docosahexaenoic Acid Ameliorates and Prevent -Related Resistance via EP4 receptor Jie-Hong Wang (5123) 11/11/2015 Outline 1. Introduction 2. Omega-3 Fatty Acids Reduce Adipose Tissue Macrophages in Human Subjects with Insulin Resistance

3. The Fish Oil Ingredient, Docosahexaenoic Acid, Activates Cytosolic Phospholipase A2 via GPR120 Receptor to Produce Prostaglandin E2 and Plays an Anti-Inflammatory Role in Macrophages

4. The Prostaglandin E2 Receptor EP4 Regulates Obesity-Related Inflammation and Insulin Sensitivity 5. Conclusion

Abstract In past few years, the development rate of obesity had been increasing in a constant rate. Obesity is known as one of the causes of many systemic and metabolic diseases. It is related to the development of Insulin Resistance which may lead to Type II Diabetes Mellitus. The main cause of the development of Insulin Resistance is chronic inflammation promoted by obese adipose tissue, which contains pro-inflammatory macrophages. As the adipose tissue grow, it releases cytokines and chemokines which recruit macrophages to infiltrate into adipose tissue and polarized into pro-inflammatory types of macrophages via induction of inflammatory cytokines. DHA, Docosahexaenoic Acid, is one of n-3 polyunsaturated fatty acids which can be found in fish oils. It has been studied and shown to have benefits on human body, which one of its benefits is the amelioration of inflammation. The signaling pathway of DHA to anti- inflammatory effect is complicated, but it is certainly involved the production of eicosanoids. These eicosanoids are said to be interact with one of their receptors, EP4, which then activate the anti-inflammatory signaling cascades. Present study uses DHA to observe the effect on obesity-induced inflammation and the anti- inflammatory responses by macrophages. We found that n-3 PUFA may decrease adipose tissue inflammation in dose dependent manner. We also figured out one of the possible pathway in DHA ameliorating inflammation is through the activation of EP4 receptor. This pathway might able to ameliorate insulin resistance in Type II Diabetes Mellitus.

References Ahmad, R.S., Butt, M.S., Sultan, M.T., Mushtaq, Z., Ahmad, S., Dewanjee, S., De Feo, V., Zia-Ul-Haq, M., 2015. Preventive role of green tea catechins from obesity and related disorders especially hypercholesterolemia and hyperglycemia. Journal of Translational Medicine 13, 79. Casula, M., Soranna, D., Catapano, A.L., Corrao, G., 2013. Long-term effect of high dose omega-3 fatty acid supplementation for secondary prevention of cardiovascular outcomes: A meta-analysis of randomized, placebo controlled trials. Atherosclerosis Supplements 14, 243-251. Coleman, R.A., Smith, W.L., Narumiya, S., 1994. International Union of Pharmacology classification of prostanoid receptors: properties, distribution, and structure of the receptors and their subtypes. Pharmacology Review 46, 205-229. Gustafson, B., Hammarstedt, A., Andersson, C.X., Smith, U., 2007. Inflamed adipose tissue: a culprit underlying the metabolic syndrome and atherosclerosis. Arteriosclerosis, Thrombosis, and Vascular Biology 27, 2276-2283. Hoyer, D., Clarke, D.E., Fozard, J.R., Hartig, P., Martin, G.R., Mylecharane, E.J., Saxena, P.R., Humphrey, P., 1994. International Union of Pharmacology classification of receptors for 5- hydroxytryptamine (Serotonin). Pharmacological Reviews 46, 157-203. Li, K., Huang, T., Zheng, J., Wu, K., Li, D., 2014. Effect of marine-derived n-3 polyunsaturated fatty acids on C-reactive , interleukin 6 and tumor necrosis factor alpha: a meta-analysis. PLoS One 9, e88103. Liu, Y., Chen, L.Y., Sokolowska, M., Eberlein, M., Alsaaty, S., Martinez-Anton, A., Logun, C., Qi, H.Y., Shelhamer, J.H., 2014. The fish oil ingredient, docosahexaenoic acid, activates cytosolic

phospholipase A2 via GPR120 receptor to produce prostaglandin E2 and plays an anti- inflammatory role in macrophages. Immunology 143, 81-95. Lumeng, C.N., Bodzin, J.L., Saltiel, A.R., 2007. Obesity induces a phenotypic switch in adipose tissue macrophage polarization. The Journal of Clinical Investigation 117, 175-184. MacLean, C.H., Newberry, S.J., Mojica, W.A., Khanna, P., Issa, A.M., Suttorp, M.J., Lim, Y.W., Traina, S.B., Hilton, L., Garland, R., Morton, S.C., 2006. Effects of omega-3 fatty acids on cancer risk: a systematic review. Journal of the American Medical Association 295, 403-415. Nataraj, C., Thomas, D.W., Tilley, S.L., Nguyen, M., Mannon, R., Koller, B.H., Coffman, T.M., 2001.

Receptors for prostaglandin E2 that regulate cellular immune responses in the mouse. Journal of Clinical Investigation 108, 1229. Needleman, P., Jakschik, B., Morrison, A., Lefkowith, J., 1986. Arachidonic acid metabolism. Annual Review of Biochemistry 55, 69-102. Ruxton, C.H., Calder, P.C., Reed, S.C., Simpson, M.J., 2005. The impact of long-chain n-3 polyunsaturated fatty acids on human health. Nutrition Research Review 18, 113-129. Schug, T.T., Li, X., 2009. PPARδ-mediated macrophage activation: a matter of fat. Disease Models and Mechanisms 2, 421-422. Shen, S. C., Chang, W. C., & Chang, C. L., 2012. Fraction from wax apple [Syzygium samarangense (Blume) Merrill and Perry] fruit extract ameliorates insulin resistance via modulating insulin signaling and inflammation pathway in tumor necrosis factor α-treated FL83B mouse hepatocytes. International journal of molecular sciences 13(7), 8562-8577. Spencer, M., Finlin, B.S., Unal, R., Zhu, B., Morris, A.J., Shipp, L.R., Lee, J., Walton, R.G., Adu, A., Erfani, R., Campbell, M., McGehee, R.E., Jr., Peterson, C.A., Kern, P.A., 2013. Omega-3 fatty acids reduce adipose tissue macrophages in human subjects with insulin resistance. Diabetes 62, 1709-1717. Xu, H., Barnes, G.T., Yang, Q., Tan, G., Yang, D., Chou, C.J., Sole, J., Nichols, A., Ross, J.S., Tartaglia, L.A., Chen, H., 2003. Chronic inflammation in fat plays a crucial role in the development of obesity-related insulin resistance. Journal of Clinical Investigation 112, 1821-1830. Yasui, M., Tamura, Y., Minami, M., Higuchi, S., Fujikawa, R., Ikedo, T., Nagata, M., Arai, H.,

Murayama, T., Yokode, M., 2015. The prostaglandin E2 receptor EP4 regulates obesity-related inflammation and insulin sensitivity. PLoS One 10, e0136304.