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This Article Full Text Full Text (PDF) Supplemental Figures All Versions of this Article: 297/1/E202    most recent 90865.2008v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Morton, G. J. Articles by Figlewicz, D. P. PubMed PubMed Citation Articles by Morton, G. J. Articles by Figlewicz, D. P.

The action of leptin in the ventral tegmental area to decrease food intake is dependent on Jak-2 signaling

¹Diabetes and Obesity Center of Excellence, Department of Medicine and ³Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle; and ²Veterans Affairs Puget Sound Health Care System, Office of Research and Development Medical Research Service, Department of Veterans Affairs Medical Center, Seattle, Washington

Submitted 17 October 2008 ; accepted in final form 6 May 2009

Recent evidence suggests that leptin reduces food intake via actions in the brain circuitry of food reward, such as the ventral tegmental area (VTA), as leptin receptors are present in the VTA, and leptin injection in the VTA reduces food intake. In the hypothalamus, leptin-induced anorexia requires signaling via Janus kinase-signal transducer and activator of transcription (Jak-STAT), insulin receptor substrate (IRS)-phosphatidylinositol 3-kinase (PI 3-kinase), and mammalian target of rapamycin (mTOR). In this study, we determined whether leptin activates each of these signal transduction pathways in the VTA and whether these signaling pathways are required for VTA-leptin induced anorexia. Here, we show that pSTAT3-Tyr⁷⁰⁵, a marker of leptin activation, was induced in a midbrain region containing the VTA and substantia nigra following either intracerebroventricular leptin or direct administration of leptin to the VTA, but these interventions failed to increase levels of either pAKT-Ser⁴⁷³ or phospho-p70S6K-Thr³⁸⁹, markers of IRS-PI 3-kinase and mTOR signaling, respectively. Moreover, the effect of intra-VTA leptin administration to reduce 4- and 20-h food intake and 20-h body weight was blocked by an inhibitor of Jak-2, at a dose that had no effect on food intake or body weight by itself, but not by local inhibition of either PI 3-kinase (LY-294002) or mTOR (rapamycin) in this timeframe. Taken together, these data support the hypothesis that leptin signaling in the VTA is involved in the regulation of energy balance, but, in contrast to the leptin signaling in the hypothalamus, these effects are mediated predominantly via Jak-2 signaling rather than via the IRS-PI 3-kinase or mTOR signaling pathway.

leptin; food intake; ventral tegmental area; signal transducer and activator of transcription signaling