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Abstract: Leptin resistance associated with hyperleptinemia in high-fat-diet-induced obese rats and aged obese rats is well established, but it is not clear whether hyperphagia-induced obese rats also develop leptin resistance. We investigated whether Otsuka Long-Evans Tokushima Fatty (OLETF) rats, which are a strain of hyperphagia-induced obese rats, develop leptin resistance and whether caloric restriction reversed this leptin resistance-induced leptin receptor (ObRb) deficit. Twenty male OLETF rats, 20 male Long-Evans Tokushima Otsuka (LETO) rats, and 10 male Sprague Dawley (SD) rats were used. All rats were initially studied at 10weeks of age and were freely fed with standard rat chow and water until they were 38weeks of age. Daily food intake, body weight, and plasma leptin levels of OLETF rats were remarkably increased compared to LETO or SD rats from 10 to 38weeks of age. When they were 38weeks of age, all OLETF rats were randomly divided into two groups. One group was freely fed with standard rat chow (FD, or free diet group), and the other group (RD, or restricted diet group) was fed with only 70% of the amount consumed by the FD group. The LETO and SD rats were dismissed from further study. After 4weeks of caloric restriction, the average body weight (636±33g vs. 752±24g, P <0.05) and abdominal adipose tissue weight (10.6±3.2g vs. 15.8±1.5g, P <0.05) of the RD group were decreased compared with those of the FD group. Plasma leptin levels of the RD group were significantly decreased compared with those of the FD group (3.47±1.40ng/mL vs. 11.55±1.16ng/mL, P <0.05). The mRNA expression of ObRb and leptin-related suppressor of cytokine signaling 3 (SOCS3) in the hypothalamus, liver, and skeletal muscles of the RD group were significantly decreased compared with those of the FD group. Caloric restriction did not improve leptin receptor (ObRb) deficit or the downstream signaling of leptin in the liver, skeletal muscles, and hypothalamus. Thus, we demonstrated that OLETF rats, which are a strain of hyperphagia-induced obese rats, did not develop central or peripheral leptin resistance. We suggest that hyperleptinemia in OLETF rats is a compensatory mechanism to overcome obesity induced by hyperphagia. [Copyright &y& Elsevier]