Rottlerin Inhibits Insulin-Stimulated Glucose Transport in 3T3-L1 Adipocytes by Uncoupling Mitochondrial Oxidative Phosphorylation

• Published in: Endocrinology (Philadelphia) 2002-10, Vol.143 (10), p.3884-3896
• Main Authors: Kayali, Ayse G, Austin, Darrell A, Webster, Nicholas J. G
• Format: Article
• Language: English
• Subjects: 3T3 Cells; Acetophenones - pharmacology; Adenosine triphosphate; Adipocytes; Adipocytes - metabolism; Adipose tissue; Animal tissues; Animals; ATP; Benzopyrans - pharmacology; Biological Transport - drug effects; Enzyme Activation - drug effects; Enzyme Inhibitors - pharmacology; Glucose; Glucose - metabolism; Glucose transport; Hepatocytes; Hypoglycemic Agents - pharmacology; Insulin; Insulin - pharmacology; Isoenzymes - antagonists & inhibitors; Isoenzymes - metabolism; Isoforms; Kinases; Mice; Mitochondria - metabolism; Muscles; Oxidative phosphorylation; Oxidative Phosphorylation - drug effects; Phosphorylation; Protein kinase C; Protein Kinase C - antagonists & inhibitors; Protein Kinase C - metabolism; Protein Kinase C-delta; Protein transport; Proteins; Tissue Distribution; Uncoupling Agents - pharmacology
• ISSN: 0013-7227; 1945-7170
• DOI: 10.1210/en.2002-220259

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 PKCδ mediates some of insulin’s actions in muscle and liver cells. Many studies use the specific inhibitor rottlerin to demonstrate the involvement of PKCδ. In this study, we investigated whether PKCδ might play a role in 3T3-L1 adipocytes. We found that PKCδ 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 PKCδ are not altered by insulin, but the protein translocates to membranes following insulin treatment. In contrast to the results with rottlerin, inhibition of PKCδ 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.