Hypothalamic leptin resistance is associated with impaired leptin signal transduction in aged obese rats

Leptin contributes to the regulation of both food intake and energy expendi ture. We previously demonstrated that the F344xBN rat. a rodent model for l ate-onset obesity, is leptin-resistant and that leptin signal transduction following peripheral administration of leptin is impaired in these aged. ov erweight rats. To determine if leptin signal transduction is impaired in re sponse to central administration of leptin and whether reduced hypothalamic leptin receptors may be contributing to the impaired signal transduction, we examined the in vivo dose-response leptin-induced STAT3 activation (phos phorylation and binding activity to the SIE M-67 oligonucleotide) in respon se to i.c.v. administration of leptin along with the level of hypothalamic leptin receptor protein in young and older, late-onset obese rats. The lept in-induced maximum phosphorylation of STAT3 was 41%, greater in young compa red with older obese rats, but the dose required for half-maximal phosphory lation of STAT3 was similar in both the young (41 ng) and old-obese (47 ng) rats. There were no changes in total STAT3 protein with leptin or age, and leptin did not increase phosphorylation of STAT1. Leptin increased phospho rylation of STAT3 transcription factor binding eight-fold in the young but only four-fold in the aged-obese rats, and leptin receptor protein was 50%, greater in the young compared with aged rats. These data indicate that aged-overweight rats demonstrate reduced signal tr ansduction in response to centrally administered leptin that may be the res ult of the diminished leptin receptor protein observed in the aged-obese ra ts. The diminished leptin receptors and impaired leptin signal transduction may explain the diminished physiological responses observed following lept in administration in older rats. This impaired leptin signal transduction m ay be due either to the elevated obesity with age or to age itself, or to b oth. (C) 2001 IBRO. Published by Elsevier Science Ltd. All rights reserved.