Obesity is a consequence of imbalance of food intake and energy expenditure that results in storage of energy as fat, primarily in adipose tissue. MicroRNAs are non-coding RNAs that regulate gene expression in metabolic pathways and they are also involved in fat-cell development. The aim of this study was to evaluate whether microRNA dysfunction contributes to obesity. We analyzed, by microarray, the expression profile of 1,458 microRNAs in subcutaneous adipose tissue (SAT) from nondiabetic severely obese (n = 20) and nonobese adults (n = 8). Among 42 differently expressed microRNAs, we confirmed by reverse-transcription PCR (RT-PCR) that miR-519d was overexpressed whereas the protein levels of peroxisome proliferator-activated receptor-α (PPARA) (a predicted miR 519d target) were lower, at western analysis, in severely obese vs. nonobese subjects. We also show that miR-519d specifically and dose-dependently suppressed translation of the PPARA protein, and increased lipid accumulation during preadipocyte differentiation. Because PPARA plays a central role in fatty acid homeostasis, and in the transcriptional regulation of genes that are necessary for maintenance of the redox balance during the oxidative catabolism of fatty acids, we suggest that PPARA loss and miR-519d overexpression could be associated with metabolic imbalance and subsequent adipocyte hypertrophy in SAT during obesity.