Impaired leptin signal transduction with age-related obesity.
Leptin contributes to the regulation of both food intake and energy expenditure. We previously demonstrated that the F-344xBN 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 microg) compared with young (26 microg) 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.
Scarpace
P J
PJ
Geriatric Research, Education and Clinical Center, Department of Veterans Affairs Medical Center, FL, Gainesville 32608-1197, USA. scarpace@ufl.edu
Matheny
M
M
Shek
E W
EW
D000375:Aging; D000818:Animals; D001667:Binding, Competitive; D004268:DNA-Binding Proteins / Q000187:drug effects / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D007031:Hypothalamus / Q000378:metabolism; D020738:Leptin / Q000097:blood / Q000494:pharmacology*; D008297:Male; D051379:Mice; D009765:Obesity / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D051381:Rats; D011914:Rats, Inbred BN; D011916:Rats, Inbred F344; D050794:STAT1 Transcription Factor; D050796:STAT3 Transcription Factor; D015398:Signal Transduction / Q000187:drug effects*; D013997:Time Factors; D015534:Trans-Activators / Q000187:drug effects / Q000378:metabolism
D004268:DNA-Binding Proteins; D020738:Leptin; D050794:STAT1 Transcription Factor; D050796:STAT3 Transcription Factor; C494080:Stat1 protein, mouse; C494087:Stat3 protein, mouse; C494088:Stat3 protein, rat; D015534:Trans-Activators