Leptin is produced by adipose tissue and acts as a feedback signal to the hypothalamus controlling energy homeostasis, by reducing food consumption and increasing energy expenditure. Because serum leptin levels are highly correlated with body fat mass, they can be used as an index to predict obesity-related diseases. However, the identity of genetic factors that influence the obesity and the obesity-related metabolic disorders remains largely unknown. In this study, we performed a whole-genome scan search, using 382 F2 intercross progeny between the Otsuka Long-Evans Tokushima Fatty (OLETF) rat, an animal model for obese type 2 diabetes in human, and F344 rat, in order to identify loci responsible for the regulation of leptin and other obesity-related plasma substances. We have identified two quantitative trait loci (QTLs) contributing to serum leptin levels. These two loci, designated Olep1 [Chromosome (Chr) 2] and Olep2 (Chr 6), were homologous to those of human genome regions containing several potential candidate genes for obesity. These are fatty acid-binding protein 2 (FABP2), FABP4, and FABP5 for Olep1, and proopiomelanocortin (POMC) and glucose regulatory protein (GCKR) for Olep2.