Gastric inhibitory peptide controls adipose insulin sensitivity via activation of cAMP-response element-binding protein and p110β isoform of phosphatidylinositol 3-kinase.
Gastric inhibitory peptide (GIP) is an incretin hormone secreted in response to food intake. The best known function of GIP is to enhance glucose-dependent insulin secretion from pancreatic β-cells. Extra-pancreatic effects of GIP primarily occur in adipose tissues. Here, we demonstrate that GIP increases insulin-dependent translocation of the Glut4 glucose transporter to the plasma membrane and exclusion of FoxO1 transcription factor from the nucleus in adipocytes, establishing that GIP has a general effect on insulin action in adipocytes. Stimulation of adipocytes with GIP alone has no effect on these processes. Using pharmacologic and molecular genetic approaches, we show that the effect of GIP on adipocyte insulin sensitivity requires activation of both the cAMP/protein kinase A/CREB signaling module and p110β phosphoinositol-3' kinase, establishing a novel signal transduction pathway modulating insulin action in adipocytes. This insulin-sensitizing effect is specific for GIP because isoproterenol, which elevates adipocyte cAMP and activates PKA/CREB signaling, does not affect adipocyte insulin sensitivity. The insulin-sensitizing activity points to a more central role for GIP in intestinal regulation of peripheral tissue metabolism, an emerging feature of inter-organ communication in the control of metabolism.
Department of Biochemistry, Weill Medical College of Cornell University, New York, New York 10065, USA.
Sameer
S
Mohammad
Lavoisier S
LS
Ramos
Jochen
J
Buck
Lonny R
LR
Levin
Francesco
F
Rubino
Timothy E
TE
McGraw
D041721:3T3-L1 Cells; D017667:Adipocytes / Q000187:drug effects / Q000378:metabolism; D000273:Adipose Tissue / Q000378:metabolism*; D000818:Animals; D058543:Class Ia Phosphatidylinositol 3-Kinase / Q000378:metabolism*; D000242:Cyclic AMP / Q000378:metabolism; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism*; D004591:Electrophoresis, Polyacrylamide Gel; D005749:Gastric Inhibitory Polypeptide / Q000494:pharmacology*; D015151:Immunoblotting; D047468:Immunoprecipitation; D007333:Insulin Resistance; D051379:Mice; D011972:Receptor, Insulin / Q000378:metabolism
D017362:Cyclic AMP Response Element-Binding Protein; D005749:Gastric Inhibitory Polypeptide; D000242:Cyclic AMP; D058543:Class Ia Phosphatidylinositol 3-Kinase; D011972:Receptor, Insulin