Abstract
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.
Highlights
Gastric inhibitory peptide (GIP) is a gut hormone secreted in response to nutrient intake
Reagents and Antibodies—GIP [1,2,3,4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19,20,21,22,23,24,25,26,27,28,29,30,31,32] was purchased from Bachem, Inc. (Torrance, CA); formaldehyde, CPT-cAMP (8-(4chlorophenyl-thio)adenosine 3Ј5Ј-cyclic monophosphate), and dimethyl sulfoxide were from Sigma-Aldrich; anti-HA antibodies were from Covance (Berkley, CA); anti-Akt, anti-phosphoAkt (Ser473 and Thr308), anti-phospho-cAMPresponse element-binding protein (CREB) Ser133, anti-CREB antibodies, anti-perilipin A and anti-phospho-Ser/Thr PKA substrate antibodies were from Cell Signaling Technology (Beverly, MA); anti AS160 and anti-phospho AS160 from Millipore (Billerica, MA); Cy3-conjugated anti-mouse IgG and Cy5-conjugated anti-rabbit IgG were from Jackson ImmunoResearch Laboratories (West Grove, PA); secondary peroxidase-conjugated anti-rabbit IgG were from Pierce; H89 (2Ј,5Јdideoxyadenosine) and Akt inhibitor 1/2 (Akti) were from Calbiochem; TGX-221 was from Cayman Chemicals (Ann Arbor, Michigan), and siRNA oligonucleotides were from Invitrogen
GIP Potentiates Insulin Action in Adipocytes—The insulinstimulated glucose uptake into adipocytes is achieved by the translocation of intracellular glucose transporter-4 (Glut4) to the plasma membrane [23]
Summary
GIP is a gut hormone secreted in response to nutrient intake. Results: GIP has an insulin-sensitizing effect on adipose via activation of the cAMP/PKA/CREB and p110 PI3K. 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 p110 phosphoinositol-3 kinase, establishing a novel signal transduction pathway modulating insulin action in adipocytes. This phenomenon has been termed as incretin effect and is estimated to account for 50 –70% of the total insulin secretion after oral glucose administration [3] This is one of the key mechanisms by which the gut communicates with peripheral tissues in regulation of glucose homeostasis. We find that GIP augmentation of insulin sensitivity requires elevation of cAMP, activation of protein kinase A and functional cAMPresponse element-binding protein (CREB), as well as activation of p110 PI3K activity These data define a novel signal transduction pathway modulating insulin action in adipocytes and provide insight into the actions of GIP in adipose tissue
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