Submitted on October 17, 2008
Revised on April 16, 2009
Accepted on May 6, 2009
The Action of Leptin in the Ventral Tegmental Area to Decrease Food Intake is Dependent on Jak-2 Signaling
Gregory J. Morton1*, James E. Blevins2, Francis Kim3, Miles Matsen1, and Dianne P Figlewicz2
1 University of Washington
2 VA Puget Sound Health Care System
3 Univ. of Washington
* To whom correspondence should be addressed. E-mail: gjmorton{at}u.washington.edu.
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 into the VTA reduces food intake. In the hypothalamus, leptin-induced anorexia requires signaling via Jak-STAT, IRS-PI3K and 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 (SN) following either intracerebroventricular (i.c.v.) 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-PI3K and mTOR signaling, respectively. Moreover, the effect of intra-VTA leptin administration to reduce 4- and 20h food intake and 20h body weight was blocked by an inhibitor of Jak2, at a dose that had no effect on food intake or body weight by itself, but not by local inhibition of either PI3K (LY294002) 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 Jak2 signaling rather than via the IRS-PI3K or mTOR signaling pathway.
