Leptin inhibits hypothalamic Npy and Agrp gene expression via a mechanism that requires phosphatidylinositol 3-OH-kinase signaling.

Morrison CD, Morton GJ, Niswender KD, Gelling RW, Schwartz MW
Am J Physiol Endocrinol Metab. 2005 289 (6): E1051-7

PMID: 16046456 · DOI:10.1152/ajpendo.00094.2005

Phosphatidylinositol 3-OH-kinase (PI3K) and STAT3 are signal transduction molecules activated by leptin in brain areas controlling food intake. To investigate their role in leptin-mediated inhibition of hypothalamic neuropeptide Y (Npy) and agouti-related peptide (Agrp) gene expression, male Sprague-Dawley rats (n = 5/group) were either fed ad libitum or subjected to a 52-h fast. At 12-h intervals, the PI3K inhibitor LY-294002 (LY, 1 nmol) or vehicle was injected intracerebroventricularly (ICV) as a pretreatment, followed 1 h later by leptin (3 microg icv) or vehicle. Fasting increased hypothalamic Npy and Agrp mRNA levels (P < 0.05), and ICV leptin administration prevented this increase. As predicted, 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 immunohistochemistry and suppressor of cytokine signaling-3 (Socs3) mRNA, was not significantly attenuated by ICV LY pretreatment. Because NPY/AgRP neurons project to the hypothalamic paraventricular nucleus (PVN), we next investigated whether leptin activation of PVN neurons is similarly PI3K dependent. Compared with 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 both to 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 or Agrp in the absence of PI3K signaling.

MeSH Terms (27)

Agouti-Related Protein Animals Arcuate Nucleus of Hypothalamus Chromones Enzyme Inhibitors Fasting Gene Expression Regulation Hypothalamus Injections, Intraventricular Intercellular Signaling Peptides and Proteins Leptin Male Morpholines Neurons Neuropeptide Y Paraventricular Hypothalamic Nucleus Phosphatidylinositol 3-Kinases Phosphoinositide-3 Kinase Inhibitors Proteins Proto-Oncogene Proteins c-fos Rats Rats, Sprague-Dawley RNA, Messenger Signal Transduction STAT3 Transcription Factor Suppressor of Cytokine Signaling 3 Protein Suppressor of Cytokine Signaling Proteins

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