Obesity has become an epidemic that affects the quality of life for more than one third of the US population. Syndromes associated with obesity, such as type 2 diabetes, fatty liver disease, cardiovascular disease, and hyperlipidemia cost billions of dollars to health care annually. One such major obesity-linked syndrome is the development of insulin resistance, which can lead to other systemic complications. Studies conducted over the years indicate insulin resistance is exacerbated due to increased infiltration and chronic activation of immune cells into adipose tissue as well as many other tissues such as liver, skeletal muscle and pancreas. Therefore, targeting immune cells to reduce inflammation is an important weapon to treat obesity related syndrome. Interestingly, deficiency of fatty acid binding protein 4 (FABP4, also know as aP2) in macrophages suppresses inflammatory activation of the cells and contributes to whole body insulin sensitivity in an animal model. However, the mechanism of how FABP4 deficiency leads to the suppressed inflammatory was not well defined. In my thesis research, we identified uncoupling protein 2 (UCP2) and Sirtuin 3 (Sirt3) as important mediators of the anti-inflammatory phenotype in FABP4 deficient macrophages. Increased expression of UCP2 in FABP4 null macrophages contributes to both suppressed inflammation and endoplasmic reticulum stress (ER stress) by reducing mitochondrial production of reactive oxygen species (ROS), while Sirt3 induction contributes to suppressed inflammation, increased beta-oxidation, and improved mitochondrial function in FABP4 deficient macrophages. Interestingly, the FABP4-UCP2 axis also extends to a human bariatric surgery model. In the subcutaneous adipose tissue from patients undergoing bariatric surgery, decreased expression of FABP4 and concomitant increase of UCP2 expression was observed seven days post surgery. The increased expression of UCP2 reduced oxidative stress in the tissue and may contribute to the early on metabolic improvements in these patients.