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

Gregory J. Morton,James E. Blevins,2 Francis Kim,1 Miles Matsen,1 and Dianne P. Figlewicz

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

Recent evidence suggests that leptin reduces food intake viaactions in the brain circuitry of food reward, such as the ventraltegmental area (VTA), as leptin receptors are present in theVTA, and leptin injection in the VTA reduces food intake. Inthe hypothalamus, leptin-induced anorexia requires signalingvia Janus kinase-signal transducer and activator of transcription(Jak-STAT), insulin receptor substrate (IRS)-phosphatidylinositol3-kinase (PI 3-kinase), and mammalian target of rapamycin (mTOR).In this study, we determined whether leptin activates each ofthese signal transduction pathways in the VTA and whether thesesignaling 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 substantianigra following either intracerebroventricular leptin or directadministration of leptin to the VTA, but these interventionsfailed 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 reduce4- and 20-h food intake and 20-h body weight was blocked byan inhibitor of Jak-2, at a dose that had no effect on foodintake or body weight by itself, but not by local inhibitionof either PI 3-kinase (LY-294002) or mTOR (rapamycin) in thistimeframe. Taken together, these data support the hypothesisthat leptin signaling in the VTA is involved in the regulationof energy balance, but, in contrast to the leptin signalingin the hypothalamus, these effects are mediated predominantlyvia Jak-2 signaling rather than via the IRS-PI 3-kinase or mTORsignaling pathway.

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


source : Diabetes 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

Pediatric Articles Dr Widodo Judarwanto (pediatrician)

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