Impaired leptin signal transduction with age-related obesity

Abstract

Leptin contributes to the regulation of both food intake and energy expenditure. We previously demonstrated that the F-344×BN rat, a rodent model for late-onset obesity, is leptin resistant, suggesting that leptin signal transduction may be impaired in these aged, overweight rats. To test this hypothesis, we examined the in vivo dose–response and time–course response of leptin-induced STAT3 activation (phosphorylation and binding activity to the SIE M67 oligonucleotide) in the hypothalamus of young rats along with the dose–response leptin-induced STAT3 phosphorylation (P-STAT3) and maximum increase 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 binding 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 unchanged with age, but the dose for half maximal phosphorylation was greater in aged (138 μg) compared with young (26 μg) 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, demonstrate a time and dose response increase paralleling the rise and fall in serum leptin, suggesting that serum leptin levels are the most important factor in determining leptin-induced phosphorylation of STAT3 in the hypothalamus. In addition, aged, overweight rats demonstrate reduced signal transduction in response to leptin, with reduced sensitivity for STAT3 phosphorylation and diminished leptin-induced P-STAT3 transcription factor binding. This impaired leptin signal transduction may be due to either the elevated obesity with age or due to age itself or both.