Effects of mitochondrial uncoupling on adipocyte intracellular Ca(2+) and lipid metabolism.
Previous data from this laboratory demonstrate that increased intracellular Ca(2+) ([Ca(2+)]i) coordinately regulates human and murine adipocyte lipid metabolism by stimulating lipogenesis and inhibiting lipolysis. However, recent data demonstrate metabolic uncoupling increases [Ca(2+)]i but inhibits lipogenesis by suppressing fatty acid synthase (FAS) activity. Accordingly, we have evaluated the interaction between mitochondrial uncoupling, adipocyte [Ca(2+)]i, and adipocyte lipid metabolism. Pretreatment of 3T3-L1 cells with mitochondrial uncouplers (DNP or FCCP) amplified the [Ca(2+)]i response to depolarization with KCl by 2-4 fold (p <0.001), while this increase was prevented by [Ca(2+)]i channel antagonism with lanthanum. Mitochondrial uncouplers caused rapid (within 4hr) dose-dependent inhibition of FAS activity (p <0.001), while lanthanum caused a further additive inhibition. The suppression of FAS activity induced by uncoupling was reversed by addition of ATP. Mitochondrial uncouplers increased FAS expression significantly while [Ca(2+)]i antagonism with lanthanum decreased FAS expression (P <0.001). In contrast, mitochondrial uncouplers independently inhibited basal and isoproterenol-stimulated lipolysis (20-40%, p <0.001), while this inhibition was fully reversed by lanthanum. Thus, mitochondrial uncoupling exerted short-term regulatory effects on adipocyte [Ca(2+)]i and lipogenic and lipolytic systems, serving to suppress lipolysis via a Ca(2+) -dependent mechanism and FAS activity via a Ca(2+)-independent mechanism.
Sun
Xiaocun
X
University of Tennessee, Knoxville, TN 37996, USA.
Zemel
Michael B
MB
D019297:2,4-Dinitrophenol / Q000494:pharmacology; D041721:3T3-L1 Cells; D000255:Adenosine Triphosphate / Q000494:pharmacology; D017667:Adipocytes / Q000187:drug effects* / Q000378:metabolism* / Q000648:ultrastructure; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D002121:Calcium Channel Blockers / Q000494:pharmacology; D002259:Carbonyl Cyanide p-Trifluoromethoxyphenylhydrazone / Q000494:pharmacology; D002352:Carrier Proteins / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D064429:Fatty Acid Synthases / Q000037:antagonists & inhibitors / Q000378:metabolism; D007473:Ion Channels; D007811:Lanthanum / Q000494:pharmacology; D050356:Lipid Metabolism; D008066:Lipolysis / Q000187:drug effects; D008565:Membrane Proteins / Q000502:physiology; D051379:Mice; D008928:Mitochondria / Q000502:physiology; D024101:Mitochondrial Proteins; D014475:Uncoupling Agents / Q000494:pharmacology*; D000071256:Uncoupling Protein 1
D002121:Calcium Channel Blockers; D002352:Carrier Proteins; D004791:Enzyme Inhibitors; D007473:Ion Channels; D008565:Membrane Proteins; D024101:Mitochondrial Proteins; D014475:Uncoupling Agents; D000071256:Uncoupling Protein 1; D002259:Carbonyl Cyanide p-Trifluoromethoxyphenylhydrazone; D007811:Lanthanum; D000255:Adenosine Triphosphate; D064429:Fatty Acid Synthases; D019297:2,4-Dinitrophenol; D002118:Calcium