title: Potentiation of glucose uptake in 3T3-L1 adipocytes by PPAR gamma agonists is maintained in cells expressing a PPAR gamma dominant-negative mutant: evidence for selectivity in the downstream responses to PPAR gamma activation.
abstract: Pharmacological agonists for the nuclear receptor PPAR gamma enhance glucose disposal in a variety of insulin-resistant states in humans and animals. The precise mechanisms whereby activation of PPAR gamma leads to increased glucose uptake in metabolically active cells remain to be determined. Notably, certain novel, synthetic PPAR gamma 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 gamma 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 gamma, which was demonstrated to strongly inhibit adipogenesis, completely failed to inhibit rosiglitazone-stimulated glucose uptake. Similar findings were obtained with the non-thiazolidinedione PPAR gamma agonists, GW1929 and GW7845. The insensitivity of PPAR gamma 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 gamma activation to downstream events may differ depending on the nature of the biological response. The growing evidence that the effects of PPAR gamma on adipogenesis and glucose uptake can be dissociated may have important implications for the development of improved antidiabetic drug treatments.
authors.affiliation: Department of Clinical Biochemistry, University of Cambridge, Addenbrooke's Hospital, Cambridge, United Kingdom, CB2 2QR.
authors.forename: C
authors.initials: C
authors.lastname: Nugent
authors.forename: J B
authors.initials: JB
authors.lastname: Prins
authors.forename: J P
authors.initials: JP
authors.lastname: Whitehead
authors.forename: D
authors.initials: D
authors.lastname: Savage
authors.forename: J M
authors.initials: JM
authors.lastname: Wentworth
authors.forename: V K
authors.initials: VK
authors.lastname: Chatterjee
authors.forename: S
authors.initials: S
authors.lastname: O'Rahilly
mesh_terms: D016475:3T3 Cells; D000256:Adenoviridae / Q000235:genetics; D017667:Adipocytes / Q000187:drug effects* / Q000378:metabolism*; D000818:Animals; D001577:Benzophenones / Q000494:pharmacology; D002462:Cell Membrane / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism; D004357:Drug Synergism; D015870:Gene Expression; D005947:Glucose / Q000378:metabolism*; D051272:Glucose Transporter Type 1; D051275:Glucose Transporter Type 4; D049452:Green Fluorescent Proteins; D007004:Hypoglycemic Agents / Q000494:pharmacology; D007328:Insulin / Q000494:pharmacology; D008164:Luminescent Proteins / Q000235:genetics; D051379:Mice; D009004:Monosaccharide Transport Proteins / Q000032:analysis / Q000378:metabolism; D009124:Muscle Proteins; D009154:Mutation; D010080:Oxazoles / Q000494:pharmacology; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists* / Q000235:genetics* / Q000502:physiology; D000077154:Rosiglitazone; D013844:Thiazoles / Q000494:pharmacology; D045162:Thiazolidinediones; D014157:Transcription Factors / Q000819:agonists* / Q000235:genetics* / Q000502:physiology; D014162:Transfection; D014443:Tyrosine / Q000031:analogs & derivatives* / Q000494:pharmacology
chemical_list: D001577:Benzophenones; D051272:Glucose Transporter Type 1; D051275:Glucose Transporter Type 4; D007004:Hypoglycemic Agents; D007328:Insulin; D008164:Luminescent Proteins; D009004:Monosaccharide Transport Proteins; D009124:Muscle Proteins; D010080:Oxazoles; D018160:Receptors, Cytoplasmic and Nuclear; C495678:Slc2a1 protein, mouse; C495693:Slc2a4 protein, mouse; D013844:Thiazoles; D045162:Thiazolidinediones; D014157:Transcription Factors; D000077154:Rosiglitazone; D049452:Green Fluorescent Proteins; C401311:GW 7845; D014443:Tyrosine; D005947:Glucose; C120099:GW 1929