- Fatty Acid Binding Protein 4 (FABP4, aP2) is a cytoplasmic fatty acid chaperone, expressed primarily in adipocytes and myeloid cells and implicated in the development of insulin resistance and atherosclerosis. Here we demonstrate that FABP4 triggers the ubiquitination and subsequent proteasomal degradation of PPARγ, a master regulator of adipogenesis and insulin responsiveness. Importantly, FABP4-null mouse pre-adipocytes as well as macrophages exhibited increased expression of PPARγ, and complementation of FABP4 in the macrophages reversed the increase in FABP4 expression. The FABP4-null pre-adipocytes exhibited a remarkably enhanced adipogenesis compared to WT cells, indicating that FABP4 regulates adipogenesis by down-regulating PPARγ. We found that FABP4 level was higher and PPARγ level was lower in human visceral fat and mouse epididymal fat compared with their subcutaneous fat. Furthermore, FABP4 was higher in adipose tissues of obese diabetic individuals compared to healthy ones. Suppression of PPARγ by FABP4 in visceral fat may explain the reported role of FABP4 in the development of obesity-related morbidities, including insulin resistance, diabetes, and atherosclerosis.