Elsevier

Neuroscience

Volume 104, Issue 4, 3 July 2001, Pages 1111-1117
Neuroscience

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

https://doi.org/10.1016/S0306-4522(01)00142-7Get rights and content

Abstract

Leptin contributes to the regulation of both food intake and energy expenditure. We previously demonstrated that the F344×BN rat, a rodent model for late-onset obesity, is leptin-resistant and that leptin signal transduction following peripheral administration of leptin is impaired in these aged, overweight rats. To determine if leptin signal transduction is impaired in response 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 (phosphorylation and binding activity to the SIE M67 oligonucleotide) in response 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 leptin-induced maximum phosphorylation of STAT3 was 41% greater in young compared with older obese rats, but the dose required for half-maximal phosphorylation 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 phosphorylation 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 transduction in response to centrally administered leptin that may be the result of the diminished leptin receptor protein observed in the aged-obese rats. The diminished leptin receptors and impaired leptin signal transduction may explain the diminished physiological responses observed following leptin administration in older rats. This impaired leptin signal transduction may be due either to the elevated obesity with age or to age itself, or to both.

Section snippets

Animals

Six- and 24-month-old, male, F344×Brown Norway rats were obtained from Harlan Sprague–Dawley (Indianapolis, IN, USA). Upon arrival, rats were examined and remained in quarantine for 1 week. Animals were cared for in accordance with the principles of the Guide to the Care and Use of Experimental Animals. All efforts were made to minimize the number of animals used and their suffering. Rats were housed individually in micro-isolated cages with a 12:12-h light:dark cycle (07.00 to 19.00 h) and

Dose–response phosphorylation of STAT3 in young and old rats

The tyrosine phosphorylation of STAT3 following i.c.v. leptin administration was determined in hypothalamic lysates by specific immunoreactivity of P-STAT3. In our previous study, we determined that following an i.v. bolus of leptin, maximal levels of P-STAT3 were achieved 1 h post injection (Scarpace et al., 2000b). Similarly, in the present study, following administration of 15 μg leptin, i.c.v., levels of P-STAT3 were greater at 60 min compared with 30 min post injection (data not shown). To

Discussion

The leptin receptor, a member of the class I cytokine receptor family (Tarttaglia, 1997), has signal transduction properties that involve members of the JAK family of enzymes and the STAT proteins. Ligand binding initiates a sequence of events that involves receptor dimerization, JAK autophosphorylation and activation, JAK-mediated receptor phosphorylation, and JAK-mediated tyrosine phosphorylation of STAT3 protein. Subsequently, P-STAT3 proteins dimerize, bind to specific DNA sequences, and

Acknowledgements

Supported by the Medical Research Service of the Department of Veterans Affairs and National Institute on Aging Grant AG-11465.

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