PPARβ/δ ameliorates fructose-induced insulin resistance in adipocytes by preventing Nrf2 activation.
We studied whether PPARβ/δ deficiency modifies the effects of high fructose intake (30% fructose in drinking water) on glucose tolerance and adipose tissue dysfunction, focusing on the CD36-dependent pathway that enhances adipose tissue inflammation and impairs insulin signaling. Fructose intake for 8 weeks significantly increased body and liver weight, and hepatic triglyceride accumulation in PPARβ/δ-deficient mice but not in wild-type mice. Feeding PPARβ/δ-deficient mice with fructose exacerbated glucose intolerance and led to macrophage infiltration, inflammation, enhanced mRNA and protein levels of CD36, and activation of the JNK pathway in white adipose tissue compared to those of water-fed PPARβ/δ-deficient mice. Cultured adipocytes exposed to fructose also exhibited increased CD36 protein levels and this increase was prevented by the PPARβ/δ activator GW501516. Interestingly, the levels of the nuclear factor E2-related factor 2 (Nrf2), a transcription factor reported to up-regulate Cd36 expression and to impair insulin signaling, were increased in fructose-exposed adipocytes whereas co-incubation with GW501516 abolished this increase. In agreement with Nrf2 playing a role in the fructose-induced CD36 protein level increases, the Nrf2 inhibitor trigonelline prevented the increase and the reduction in insulin-stimulated AKT phosphorylation caused by fructose in adipocytes. Protein levels of the well-known Nrf2 target gene
quinone oxidoreductase 1 (Nqo1) were increased in water-fed PPARβ/δ-null mice, suggesting that PPARβ/δ deficiency increases Nrf2 activity; and this increase was exacerbated in fructose-fed PPARβ/δ-deficient mice. These findings indicate that the combination of high fructose intake and PPARβ/δ deficiency increases CD36 protein levels via Nrf2, a process that promotes chronic inflammation and insulin resistance in adipose tissue.
Pharmacology Unit, Department of Pharmacology and Therapeutic Chemistry and Institut de Biomedicina de la UB (IBUB), Faculty of Pharmacy, University of Barcelona, Barcelona, Spain; CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM)-Instituto de Salud Carlos III, Barcelona, Spain.
Emma
E
Barroso
Pharmacology Unit, Department of Pharmacology and Therapeutic Chemistry and Institut de Biomedicina de la UB (IBUB), Faculty of Pharmacy, University of Barcelona, Barcelona, Spain.
Rosalía
R
Rodríguez-Rodríguez
CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM)-Instituto de Salud Carlos III, Barcelona, Spain; Endocrinology and Diabetes Unit, Research Department, University Hospital of Tarragona Joan XXIII, Pere Virgili Institute, Tarragona, Spain; Rovira i Virgili University, Tarragona, Spain.
Matilde R
MR
Chacón
CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM)-Instituto de Salud Carlos III, Barcelona, Spain; Endocrinology and Diabetes Unit, Research Department, University Hospital of Tarragona Joan XXIII, Pere Virgili Institute, Tarragona, Spain; Rovira i Virgili University, Tarragona, Spain.
Elsa
E
Maymó-Masip
Pharmacology Unit, Department of Pharmacology and Therapeutic Chemistry and Institut de Biomedicina de la UB (IBUB), Faculty of Pharmacy, University of Barcelona, Barcelona, Spain.
Laura
L
Ferrer
Pharmacology Unit, Department of Pharmacology and Therapeutic Chemistry and Institut de Biomedicina de la UB (IBUB), Faculty of Pharmacy, University of Barcelona, Barcelona, Spain; Lee Kong Chian School of Medicine, Nanyang Technological University, The Academia, 20 College Road, 169856, Singapore.
Laia
L
Salvadó
Pharmacology Unit, Department of Pharmacology and Therapeutic Chemistry and Institut de Biomedicina de la UB (IBUB), Faculty of Pharmacy, University of Barcelona, Barcelona, Spain.
Emilio
E
Salmerón
Divisions of Paediatric Endocrinology and Diabetes, Ulm University, Ulm, Germany.
Martin
M
Wabistch
Pharmacology Unit, Department of Pharmacology and Therapeutic Chemistry and Institut de Biomedicina de la UB (IBUB), Faculty of Pharmacy, University of Barcelona, Barcelona, Spain; Lee Kong Chian School of Medicine, Nanyang Technological University, The Academia, 20 College Road, 169856, Singapore.
Xavier
X
Palomer
CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM)-Instituto de Salud Carlos III, Barcelona, Spain; Endocrinology and Diabetes Unit, Research Department, University Hospital of Tarragona Joan XXIII, Pere Virgili Institute, Tarragona, Spain; Rovira i Virgili University, Tarragona, Spain.
Joan
J
Vendrell
Center for Integrative Genomics, National Research Center Frontiers in Genetics, University of Lausanne, Quartier UNIL-Sorge, Bâtiment Génopode, CH-1015 Lausanne, Switzerland; Lee Kong Chian School of Medicine, Nanyang Technological University, The Academia, 20 College Road, 169856, Singapore.
Walter
W
Wahli
Pharmacology Unit, Department of Pharmacology and Therapeutic Chemistry and Institut de Biomedicina de la UB (IBUB), Faculty of Pharmacy, University of Barcelona, Barcelona, Spain; Lee Kong Chian School of Medicine, Nanyang Technological University, The Academia, 20 College Road, 169856, Singapore. Electronic address: mvazquezcarrera@ub.edu.
Manuel
M
Vázquez-Carrera
D041721:3T3-L1 Cells; D017667:Adipocytes / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D000470:Alkaloids / Q000494:pharmacology; D000818:Animals; D018955:CD36 Antigens / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D005632:Fructose / Q000494:pharmacology*; D018149:Glucose Intolerance / Q000235:genetics; D006801:Humans; D015151:Immunoblotting; D007333:Insulin Resistance; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D008077:Lipoproteins, LDL / Q000378:metabolism; D008297:Male; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D051267:NF-E2-Related Factor 2 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D047494:PPAR delta / Q000819:agonists / Q000235:genetics / Q000378:metabolism*; D048068:PPAR-beta / Q000819:agonists / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects; D013844:Thiazoles / Q000494:pharmacology
D000470:Alkaloids; D018955:CD36 Antigens; D016207:Cytokines; C425931:GW 501516; D008077:Lipoproteins, LDL; D051267:NF-E2-Related Factor 2; D047494:PPAR delta; D048068:PPAR-beta; D013844:Thiazoles; C099252:oxidized low density lipoprotein; D005632:Fructose; C009560:trigonelline; D048031:JNK Mitogen-Activated Protein Kinases
Adipocyte; CD36; Fructose; JNK; Oxidized LDL; PPARβ/δ