Leptin inhibits insulin secretion by activation of phosphodiesterase 3B.
The molecular signaling events by which leptin exerts its functions in vivo are not well delineated. Here, we show a novel leptin signaling mechanism that requires phosphoinositide 3-kinase (PI 3-kinase)-dependent activation of cyclic nucleotide phosphodiesterase 3B (PDE3B) and subsequent suppression of cAMP levels. In pancreatic beta cells, leptin causes the activation of PDE3B, which leads to marked inhibition of glucagon-like peptide-1-stimulated insulin secretion. The effect of leptin is abolished when insulin secretion is induced with cAMP analogues that cannot be hydrolyzed by PDE3B. Selective inhibitors of PDE3B and PI 3-kinase completely prevent the leptin effect on insulin secretion and cAMP accumulation. The results demonstrate that one of the physiological effects of leptin, suppression of insulin secretion, is mediated through activation of PDE3B and suggest PDE3B as a mediator of leptin action in other tissues.
Zhao
A Z
AZ
Department of Pharmacology, University of Washington, Seattle, Washington 98195, USA.
Bornfeldt
K E
KE
Beavo
J A
JA
D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000378:metabolism*; D000730:Androstadienes / Q000494:pharmacology; D000818:Animals; D002460:Cell Line; D002867:Chromones / Q000494:pharmacology; D000242:Cyclic AMP / Q000031:analogs & derivatives / Q000378:metabolism; D054684:Cyclic Nucleotide Phosphodiesterases, Type 3; D004789:Enzyme Activation / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005934:Glucagon / Q000494:pharmacology; D052216:Glucagon-Like Peptide 1; D005947:Glucose / Q000494:pharmacology; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000502:physiology; D020738:Leptin; D009025:Morpholines / Q000494:pharmacology; D010446:Peptide Fragments / Q000494:pharmacology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D018129:Phosphatidylinositol Phosphates / Q000494:pharmacology; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011498:Protein Precursors / Q000494:pharmacology; D011506:Proteins / Q000502:physiology*; D011760:Pyrrolidinones / Q000494:pharmacology; D051381:Rats; D020889:Rolipram; D015398:Signal Transduction / Q000502:physiology; D000077191:Wortmannin
D015105:3',5'-Cyclic-AMP Phosphodiesterases; D000730:Androstadienes; D002867:Chromones; D000242:Cyclic AMP; D054684:Cyclic Nucleotide Phosphodiesterases, Type 3; D004791:Enzyme Inhibitors; D005934:Glucagon; D052216:Glucagon-Like Peptide 1; D005947:Glucose; D007328:Insulin; D020738:Leptin; D009025:Morpholines; D010446:Peptide Fragments; D019869:Phosphatidylinositol 3-Kinases; D018129:Phosphatidylinositol Phosphates; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011498:Protein Precursors; D011506:Proteins; D011760:Pyrrolidinones; D020889:Rolipram; D000077191:Wortmannin; C055525:phosphatidylinositol 3-phosphate; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; C517294:Pde3b protein, rat