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

Abstract

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.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

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.

References

  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).

Download references

Acknowledgements

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.).

Author information

Correspondence to Abhiram Sahu.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Rights and permissions

Reprints and Permissions

About this article

Cite this article

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

Download citation

Further reading