Insulin and the beta3-adrenoceptor differentially regulate uncoupling protein-1 expression.
Cross-talk between insulin and the adrenergic system is important in the regulation of energy homeostasis. In cultured, differentiated mouse brown adipocytes, beta3-adrenergic stimulation induced a 4.5-fold increase in uncoupling protein-1 (UCP-1) expression, which was diminished by 25% in the presence of insulin. Beta3-adrenergic stimulation also activated mitogen-activated protein (MAP) kinase by 3.5-fold and caused a decrease in basal phosphoinositide (PI) 3-kinase activity detected in p110gamma- and Gbeta-subunit-immunoprecipitates in a time-dependent manner, whereas insulin stimulated p110alpha- and phosphotyrosine-associated PI 3-kinase activity. Inhibition of MAP kinase or PI 3-kinase potentiated the beta3-adrenergic effect on UCP-1 expression, both alone and in the presence of insulin. Thus, insulin inhibits beta3-adrenergic stimulation of UCP-1, and both MAP kinase and PI 3-kinase are negative regulatory elements in the beta3-adrenergic control of UCP-1 expression. Cross-talk between the adrenergic and insulin signaling systems and impaired regulation of UCP-1 might contribute to the development of a reduced energy balance, resulting in obesity and insulin resistance.
Klein
J
J
Research Division Joslin Diabetes Center, Harvard Medical School Boston, Massachusetts 02215, USA.
Fasshauer
M
M
Benito
M
M
Kahn
C R
CR
D017667:Adipocytes / Q000378:metabolism; D002001:Adipose Tissue, Brown / Q000378:metabolism; D000818:Animals; D002352:Carrier Proteins / Q000235:genetics*; D002478:Cells, Cultured; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects*; D007328:Insulin / Q000494:pharmacology*; D007473:Ion Channels; D008565:Membrane Proteins / Q000235:genetics*; D051379:Mice; D024101:Mitochondrial Proteins; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011943:Receptors, Adrenergic, beta / Q000502:physiology*; D022702:Receptors, Adrenergic, beta-3; D015398:Signal Transduction; D000071256:Uncoupling Protein 1
D002352:Carrier Proteins; D017868:Cyclic AMP-Dependent Protein Kinases; D004791:Enzyme Inhibitors; D007328:Insulin; D007473:Ion Channels; D008565:Membrane Proteins; D024101:Mitochondrial Proteins; D020928:Mitogen-Activated Protein Kinases; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011943:Receptors, Adrenergic, beta; D022702:Receptors, Adrenergic, beta-3; D000071256:Uncoupling Protein 1; C000604372:Ucp1 protein, mouse