Impaired leptin signal transduction with age-related obesity

Leptin contributes to the regulation of both food intake and energy expendi ture. We previously demonstrated that the F-344xBN rat, a rodent model for late-onset obesity, is leptin resistant, suggesting that leptin signal tran sduction may be impaired in these aged, overweight rats. To test this hypot hesis, we examined the in vivo dose-response and time-course response of le ptin-induced STAT3 activation (phosphorylation and binding activity to the SIE M67 oligonucleotide) in the hypothalamus of young rats along with the d ose-response leptin-induced STAT3 phosphorylation (P-STAT3) and maximum inc rease in binding activity in young and aged rats. In young rats there was a dose (0-1 mg, iv) and time dependent increase in P-STAT3 and in P-STAT3 bi nding activity. P-STAT3 paralleled the rise and fall in serum leptin levels with P-STAT3 elevated for at least 4 h with return to basal levels by 14 h after 1 mg leptin. The maximum level of leptin-induced P-STAT3 was unchang ed with age, but the dose for half maximal phosphorylation was greater in a ged (138 mu g) compared with young (26 mu g) rats. In addition, the leptin- induced increase in P-STAT3 transcription factor binding was diminished in aged rats. These data suggest that leptin signal transduction, in vivo, dem onstrate a time and dose response increase paralleling the rise and fall in serum leptin, suggesting that serum leptin levels are the most important f actor in determining leptin-induced phosphorylation of STAT3 in the hypotha lamus. In addition, aged, overweight rats demonstrate reduced signal transd uction in response to leptin, with reduced sensitivity for STAT3 phosphoryl ation and diminished leptin-induced P-STAT3 transcription factor binding. T his impaired leptin signal transduction may be due to either the elevated o besity with age or due to age itself or bath. Published by Elsevier Science Ltd.