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 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-Tyr(705), 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-Ser(473) or phospho-p70S6K-Thr(389), 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.
Morton
Gregory J
GJ
Department of Medicine, University of Washington at South Lake Union, 815 Mercer St., Box 358055, Seattle, WA 98195, USA. gjmorton@u.washington.edu
Blevins
James E
JE
Kim
Francis
F
Matsen
Miles
M
Figlewicz
Dianne P
DP
D000818:Animals; D000855:Anorexia / Q000139:chemically induced / Q000378:metabolism; D004435:Eating / Q000187:drug effects*; D004734:Energy Metabolism / Q000502:physiology; D007276:Injections, Intraventricular; D055504:Insulin Receptor Substrate Proteins / Q000378:metabolism / Q000502:physiology; D053614:Janus Kinase 2 / Q000378:metabolism / Q000502:physiology*; D020738:Leptin / Q000008:administration & dosage / Q000494:pharmacology*; D008297:Male; D008954:Models, Biological; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism / Q000502:physiology; D011494:Protein Kinases / Q000378:metabolism / Q000502:physiology; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D058570:TOR Serine-Threonine Kinases; D017557:Ventral Tegmental Area / Q000187:drug effects*
D055504:Insulin Receptor Substrate Proteins; D053614:Janus Kinase 2; D020738:Leptin; D019869:Phosphatidylinositol 3-Kinases; D011494:Protein Kinases; D058570:TOR Serine-Threonine Kinases