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1 University of Washington and Harborview Medical Center, Seattle, WA, USA; Pennington Biomedical Research Center, Baton Rouge, LA, USA
2 University of Washington and Harborview Medical Center, Seattle, WA, USA
3 University of Washington and Harborview Medical Center, Seattle, WA, USA; Vanderbilt University, Nashville, TN, USA
* To whom correspondence should be addressed. E-mail: mschwart{at}u.washington.edu.
Phosphatidylinositol 3-OH-Kinase (PI3K) and Signal Transducer and Activator of Transcription 3 (Stat3) are signal transduction molecules activated by leptin in brain areas controlling food intake. To investigate their role in leptin-mediated inhibition of hypothalamic Npy and Agrp gene expression, male Sprague Dawley rats (n=5/group) were either fed ad libitum or subjected to a 52h fast. At 12h intervals, the PI3K inhibitor LY294002 (LY, 1 nmole) or vehicle were injected intracerebroventricularly (icv) as a pretreatment, followed 1h later by leptin (3 ug icv) or vehicle. Fasting increased hypothalamic Npy and Agrp mRNA levels (P<0.05), and icv leptin administration prevented this increase. LY pretreatment blocked this inhibitory effect of leptin, such that Npy and Agrp levels in LY-leptin treated animals were similar to fasted controls. By comparison, leptin-mediated activation of hypothalamic Stat3 signaling, as measured by induction of both phospho-Stat3 and Socs3, was not significantly attenuated by icv LY pretreatment. Since NPY/AgRP neurons project to the hypothalamic paraventricular nucleus (PVN), we next investigated whether leptin activation of PVN neurons is similarly PI3K-dependent. Compared to vehicle, leptin increased the number of c-Fos positive cells within the parvocellular PVN (P = 0.001), and LY pretreatment attenuated this effect by 35% (P = 0.043). We conclude that leptin requires intact PI3K signaling to both inhibit hypothalamic Npy and Agrp gene expression and activate neurons within the PVN. In addition, these data suggest that leptin activation of Stat3 is insufficient to inhibit expression of Npy and Agrp in the absence of PI3K signaling.
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