Regulation of the Na,K-pump by leptin in 3T3-L1 fibroblasts.
Leptin, the product of the obesity (ob) gene, controls energy intake and expenditure primarily by actions on the central nervous system. However, recently it has become apparent that leptin also elicits a growing and diverse array of effects on peripheral tissues. The Na,K-pump is an electrogenic plasma membrane protein which actively extrudes 3Na+ ions and imports 2K+ ions per molecule of ATP hydrolysed. The pump is responsible for the maintenance of the electrochemical potential of all cells, which in turn drives all ion-coupled transport mechanisms. In this study we use 3T3-L1 fibroblasts to show that leptin inhibits Na,K-pump activity, as assessed by ouabain-sensitive 86Rb+ uptake. Inhibition of the Na,K-pump correlated with increased serine phosphorylation of the catalytic Na,K-pump alpha1 subunit. Upon investigation of leptin-stimulated signalling pathways using specific pharmacological inhibitors, only wortmannin prevented inhibition of the Na,K-pump by leptin. Moreover, leptin stimulated phosphotyrosine-associated PI 3-kinase activity in these cells. In summary, leptin was found to inhibit Na,K-pump activity, likely via PI 3-kinase. We propose that this effect may have wide ranging cardiovascular and metabolic implications and perhaps explain physiological effects of the hormone such as natriuresis.
Sweeney
G
G
Programme in Cell Biology, The Hospital for Sick Children, Toronto, Ontario, Canada.
Niu
W
W
Kanani
R
R
Klip
A
A
D016475:3T3 Cells; D000818:Animals; D003847:Deoxyglucose / Q000378:metabolism; D005347:Fibroblasts; D007527:Isoenzymes / Q000096:biosynthesis / Q000235:genetics; D020738:Leptin / Q000494:pharmacology*; D051379:Mice; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012414:Rubidium Radioisotopes; D015398:Signal Transduction / Q000187:drug effects; D012964:Sodium / Q000378:metabolism; D000254:Sodium-Potassium-Exchanging ATPase / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism
D003847:Deoxyglucose; D007527:Isoenzymes; D020738:Leptin; D019869:Phosphatidylinositol 3-Kinases; D012333:RNA, Messenger; D012414:Rubidium Radioisotopes; D012964:Sodium; D000254:Sodium-Potassium-Exchanging ATPase