Rottlerin inhibits insulin-stimulated glucose transport in 3T3-L1 adipocytes by uncoupling mitochondrial oxidative phosphorylation.
There is increasing evidence that protein kinase C (PKC) isoforms modulate insulin-signaling pathways in both positive and negative ways. Recent reports have indicated that the novel PKCdelta mediates some of insulin's actions in muscle and liver cells. Many studies use the specific inhibitor rottlerin to demonstrate the involvement of PKCdelta. In this study, we investigated whether PKCdelta might play a role in 3T3-L1 adipocytes. We found that PKCdelta is highly expressed in mouse adipose tissue and increased on 3T3-L1 adipocyte differentiation, and insulin-stimulated glucose transport is blocked by rottlerin. The phosphorylation state and activity of PKCdelta are not altered by insulin, but the protein translocates to membranes following insulin treatment. In contrast to the results with rottlerin, inhibition of PKCdelta activity or expression has no effect on glucose transport in adipocytes, unlike muscle cells. Lastly, we found that rottlerin lowers adenosine triphosphate levels in 3T3-L1 cells by acting as a mitochondrial uncoupler, and this is responsible for the observed inhibition of glucose transport.
Kayali
Ayse G
AG
Medical Research Service, San Diego Veterans Affairs Healthcare System, California 92161, USA.
Austin
Darrell A
DA
Webster
Nicholas J G
NJ
D016475:3T3 Cells; D000098:Acetophenones / Q000494:pharmacology*; D017667:Adipocytes / Q000378:metabolism*; D000818:Animals; D001578:Benzopyrans / Q000494:pharmacology*; D001692:Biological Transport / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005947:Glucose / Q000378:metabolism*; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D007328:Insulin / Q000494:pharmacology*; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000378:metabolism; D051379:Mice; D008928:Mitochondria / Q000378:metabolism*; D010085:Oxidative Phosphorylation / Q000187:drug effects; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism; D051745:Protein Kinase C-delta; D014018:Tissue Distribution; D014475:Uncoupling Agents / Q000494:pharmacology*; D000099293:Protein Kinase C-lambda
D000098:Acetophenones; D001578:Benzopyrans; D004791:Enzyme Inhibitors; D005947:Glucose; D007004:Hypoglycemic Agents; D007328:Insulin; D007527:Isoenzymes; D011493:Protein Kinase C; D051745:Protein Kinase C-delta; D014475:Uncoupling Agents; D000099293:Protein Kinase C-lambda; C085746:rottlerin; C497259:Prkcd protein, mouse