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Potentiation of Glucose Uptake in 3T3-L1 Adipocytes by PPAR Agonists Is Maintained in Cells Expressing a PPAR Dominant-Negative Mutant: Evidence for Selectivity in the Downstream Responses to PPAR Activation

Departments of Clinical Biochemistry and Medicine, University of Cambridge, Addenbrooke’s Hospital, Cambridge, United Kingdom, CB2 2QR

Address all correspondence and requests for reprints to: Stephen O’Rahilly, Department of Medicine, University of Cambridge, Addenbrooke’s Hospital, Cambridge, United Kingdom, CB2 2QR. E-mail: sorahill{at}hgmp.mrc.ac.uk

Pharmacological agonists for the nuclear receptor PPAR enhance glucose disposal in a variety of insulin-resistant states in humans and animals. The precise mechanisms whereby activation of PPAR leads to increased glucose uptake in metabolically active cells remain to be determined. Notably, certain novel, synthetic PPAR ligands appear to antagonize thiazolidinedione-induced adipogenesis yet stimulate cellular glucose uptake. We have explored the molecular mechanisms underlying the enhancement of glucose uptake produced by PPAR agonists in 3T3-L1 adipocytes. Rosiglitazone treatment for 48 h significantly increased basal and insulin-stimulated glucose uptake and markedly increased the cellular expression of GLUT1 but not GLUT4. Rosiglitazone increased plasma membrane levels of GLUT1, but not GLUT4, both basally and after insulin stimulation. Surprisingly, adenoviral expression of a dominant-negative mutant PPAR, which was demonstrated to strongly inhibit adipogenesis, completely failed to inhibit rosiglitazone-stimulated glucose uptake. Similar findings were obtained with the non-thiazolidinedione PPAR agonists, GW1929 and GW7845. The insensitivity of PPAR agonist-stimulated glucose uptake to expression of a dominant-negative mutant, compared with the latter’s marked inhibitory effects on preadipocyte differentiation, suggests that, as is the case for other nuclear receptors, the precise molecular mechanisms linking PPAR activation to downstream events may differ depending on the nature of the biological response. The growing evidence that the effects of PPAR on adipogenesis and glucose uptake can be dissociated may have important implications for the development of improved antidiabetic drug treatments.

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