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

Medical Research Service (A.G.K., D.A.A., N.J.G.W.), San Diego Veterans Affairs Healthcare System, San Diego, California 92161; University of California San Diego/Whittier Diabetes Program (A.G.K., N.J.G.W.) and University of California San Diego Cancer Center (N.J.G.W.), Department of Medicine, University of California, San Diego, California 92093

Address all correspondence and requests for reprints to: Nicholas J. G. Webster, Department of Medicine (0673), University of California, San Diego, 9500 Gilman Drive, La Jolla, California 92093-0673. E-mail: nwebster{at}ucsd.edu.

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

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