PROJECT SUMMARY/ABSTRACT Obesity is the dominant cause of insulin resistance in man and it is the obesity epidemic, which is driving the dramatically increased incidence of Type 2 Diabetes (T2D). Adipocyte dysfunction and chronic low-grade tissue inflammation are major causes of insulin resistance. In our recent work, we have reported that G protein- coupled receptor 120 (GPR120) is the functional receptor for omega-3 fatty acids (ω3-FAs) producing robust anti-inflammatory, insulin sensitizing effects, both in vivo and in vitro. Interestingly, human genetic variants in the GPR120 gene had been described which predispose subjects to obesity and diabetes. The amount of ω3- FAs which would have to be consumed to sustain chronic agonism of GPR120 is too high to be practical, and, thus, a high affinity, small molecule GPR120 agonist would be of potential clinical benefit. Accordingly, GPR120 is a widely studied drug discovery target within the pharmaceutical industry. Recently, we have identified a high affinity, selective, small molecule GPR120 agonist (compound A; cpdA), which exerts potent anti-inflammatory effects on macrophages in vitro, and in obese mice in vivo. GPR120 agonist treatment of HFD/obese mice results in anti-inflammatory signaling with improved glucose tolerance, decreased hyperinsulinemia, increased insulin sensitivity and decreased hepatic steatosis. This suggests that GPR120 agonists could emerge as new insulin sensitizing drugs for the treatment of T2D. Thiazolidinediones (TZDs) represent current therapeutic agents for treating insulin resistance. However, these agents (rosiglitazone and pioglitazone) are also associated with unwanted side effects, such as edema, weight gain, possible risk of heart failure, bone loss, and a possible correlation with certain cancers. While the exact mechanisms of TZD- induced insulin sensitization are not fully understood, these agents operate through PPARγ, and this subject has been extensively reviewed. Thus, both TZDs and GPR120 agonists can improve insulin resistance. Importantly, our recent preliminary data have suggested mechanisms whereby TZDs potentiate the effects of ω3-FAs at the same time that ω3-FAs potentiate the effects of TZDs, leading to a positive reinforcing system. In this project, we will explore the basic cellular mechanisms underlying the molecular interactions between PPARγ and GPR120. This concept also leads us to the novel hypothesis that the combination of PPARγ and GPR120 agonist treatment could produce additive or synergistic effects, leading to a greater degree of insulin sensitization than with either drug alone. Furthermore, combination treatment with a TZD plus a GPR120 agonist could lead to the use of much lower doses of TZDs, preserving the overall insulin sensitizing benefit, while mitigating unwanted side effects.