A phosphatidylinositol 3-kinase–phosphodiesterase 3B–cyclic AMP pathway in hypothalamic action of leptin on feeding


Using male Sprague-Dawley rats implanted with third intracerebroventricular (ICV) cannulae, we found that cilostamide, a phosphodiesterase 3 (PDE3) inhibitor, (i) reversed the established effects of leptin on food intake and body weight, (ii) blocked, at the hypothalamic level, the leptin-induced tyrosine phosphorylation of signal transducer and activator of transcription 3 (Stat3) and (iii) blocked the DNA binding of p-Stat3. Additionally, ICV administration of leptin increased hypothalamic phosphatidylinositol 3-kinase (PI3K) and PDE3B activities and decreased cyclic AMP (cAMP) concentration. These results indicate that a PI3K–PDE3B–cAMP pathway interacting with the Janus kinase 2 (Jak2)–Stat3 pathway constitutes a critical component of leptin signaling in the hypothalamus.

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Figure 1: Cilostamide, a PDE3 inhibitor, reverses the satiety action of leptin in male rats that are fed ad libitum, but RO-20-1724, a PDE4 inhibitor, does not.
Figure 2: Cilostamide reversed the effect of leptin on body weight.
Figure 3: Cilostamide reverses the effect of leptin on Stat3 activation in the hypothalamus.


  1. 1

    Friedman, J.M. & Halaas, J.L. Nature 395, 763–770 (1998).

  2. 2

    Schwartz, M.W., Woods, S.C., Porte, D. Jr., Seeley, R.J. & Baskin, D.G. Nature 404, 661–671 (2000).

  3. 3

    Zhao, A.Z. et al. J. Biol. Chem. 275, 11348–11354 (2000).

  4. 4

    Shimizu-Albergine, M., Ippolito, D.L. & Beavo, J.A. J. Neurosci. 21, 1238–1246 (2001).

  5. 5

    Gillard, E.R. et al. J. Neurosci. 18, 2646–2652 (1998).

  6. 6

    Beavo, J.A. & Reifsnyder, D.H. Trends Pharmacol. Sci. 11, 150–155 (1990).

  7. 7

    Rahn, T. et al. FEBS Lett. 350, 314–318 (1994).

  8. 8

    Ahmad, M., Flatt, P.R., Furman, B.L. & Pyne, N.J. Cell. Signal. 12, 541–548 (2000).

  9. 9

    Akabayashi, A. et al. Brain Res. 660, 323–328 (1994).

  10. 10

    Sahu, A. & Kalra, S.P. Trends in Endocr. Metab. 4, 217–224 (1993).

  11. 11

    Sheriff, S., Chance, W.T., Fischer, J.E. & Balasubramaniam, A. Mol. Pharmacol. 51, 597–604 (1997).

  12. 12

    Ahima, R.S., Saper, C.B., Flier, J.S. & Elmquist, J.K. Front. Neuroendocrinol. 21, 263–307 (2000).

  13. 13

    Sahu, A. Endocrinology 139, 795–798 (1998).

  14. 14

    Sahu, A. Endocrinology 139, 4739–4752 (1998).

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This work was supported by a National Institutes of Health grant DK 52844 (to A.S.) and a Career & Development Award from the American Diabetes Association (to A.Z.).

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Correspondence to Abhiram Sahu.

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Zhao, A., Huan, J., Gupta, S. et al. A phosphatidylinositol 3-kinase–phosphodiesterase 3B–cyclic AMP pathway in hypothalamic action of leptin on feeding. Nat Neurosci 5, 727–728 (2002). https://doi.org/10.1038/nn885

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