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Submitted on December 16, 2002
Accepted on May 20, 2003
1 Department of Cell Biology and Physiology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261
* To whom correspondence should be addressed. E-mail: asahu{at}pitt.edu.
Using a rat model of chronic central leptin infusion in which neuropeptide Y neurons develop leptin resistance we examined whether leptin signal transduction mechanism in the hypothalamus is altered during central leptin infusion. Adult male rats were infused chronically into the lateral cerebroventricle with leptin (160 ng/hr) or vehicle via Alzet pumps for 16 days. In leptin infused group, the initial decrease in food intake was followed by a recovery to their pre-leptin levels by day 16, although food intake remained significantly lower than in aCSF control; and body weight gradually decreased reaching a nadir at day 11 and remained stabilized at lower level thereafter. Phosphorylated leptin receptor and phosphorylated signal transducer and activator of transcription-3 (p-STAT3) remained elevated in association with a sustained elevation in DNA-binding activity of STAT3 in the hypothalamus throughout 16-day period of leptin infusion. However, phosphorylated Janus kinase-2 was increased during early part of leptin infusion but remained unaltered on day 16. While hypothalamic suppressors of cytokine signaling-3 (SOCS3) mRNA levels were increased throughout leptin infusion, SOCS3 protein levels were only increased on day 16. This study demonstrates a sustained elevation in hypothalamic leptin receptor signaling through JAK-STAT pathway despite an increased expression of SOCS3 during chronic central leptin infusion. We propose that an alteration in leptin signaling in the hypothalamus through pathways other than STAT3 and or a defect in downstream of STAT3 signaling may be involved in food intake recovery seen after an initial decrease during chronic central leptin infusion.
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