PPARβ/δ ameliorates fructose-induced insulin resistance in adipocytes by preventing Nrf2 activation

被引：21

作者：

Barroso, Emma ^{[1
,2
,3
]}

Rodriguez-Rodriguez, Rosalia ^{[1
,2
]}

Chacon, Matilde R. ^{[3
,4
,5
]}

Maymo-Masip, Elsa ^{[3
,4
,5
]}

Ferrer, Laura ^{[1
,2
]}

Salvado, Laia ^{[1
,2
,3
]}

Salmeron, Emilio ^{[1
,2
]}

Wabistch, Martin ^{[6
,7
]}

Palomer, Xavier ^{[1
,2
,3
]}

Vendrell, Joan ^{[3
,4
,5
]}

Wahli, Walter ^{[8
,9
]}

Vazquez-Carrera, Manuel ^{[1
,2
,3
]}

机构：

[1] Univ Barcelona, Fac Pharm, Dept Pharmacol & Therapeut Chem, Pharmacol Unit, Barcelona, Spain

[2] Univ Barcelona, Fac Pharm, IBUB, Barcelona, Spain

[3] Inst Salud Carlos III, CIBER Diabet & Enfermedades Metab Asociadas CIBER, Barcelona, Spain

[4] Univ Hosp Tarragona Joan XXIII, Pere Virgili Inst, Res Dept, Endocrinol & Diabet Unit, Tarragona, Spain

[5] Univ Rovira & Virgili, E-43007 Tarragona, Spain

[6] Univ Ulm, Div Paediat Endocrinol & Diabet, D-89069 Ulm, Germany

[7] Univ Ulm, Div Diabet, D-89069 Ulm, Germany

[8] Univ Lausanne, Quartier UNIL Sorge, Natl Res Ctr Frontiers Genet, Ctr Integrat Genom, CH-1015 Lausanne, Switzerland

[9] Nanyang Technol Univ, Lee Kong Chian Sch Med, Acad, Singapore 169856, Singapore

来源：

BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE | 2015年 / 1852卷 / 05期

关键词：

PPAR beta/delta; Adipocyte; Fructose; CD36; JNK; Oxidized LDL; ADIPOSE-TISSUE; HEPATIC STEATOSIS; GENE-EXPRESSION; MACROPHAGE POLARIZATION; TRANSCRIPTION FACTOR; RECEPTOR BETA/DELTA; VISCERAL ADIPOSITY; SKELETAL-MUSCLE; FED RATS; OBESITY;

D O I：

10.1016/j.bbadis.2015.02.010

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

We studied whether PPAR beta/delta 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 PPAR beta/delta-deficient mice but not in wild-type mice. Feeding PPAR beta/delta-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 PPAR beta/delta-deficient mice. Cultured adipocytes exposed to fructose also exhibited increased CD36 protein levels and this increase was prevented by the PPAR beta/delta 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 NAD(P)H:quinone oxidoreductase 1 (Nqo1) were increased in water-fed PPAR beta/delta-null mice, suggesting that PPAN beta/delta deficiency increases Nrf2 activity; and this increase was exacerbated in fructose-fed PPAR beta/delta-deficient mice. These findings indicate that the combination of high fructose intake and PPAR beta/delta deficiency increases CD36 protein levels via Nrf2, a process that promotes chronic inflammation and insulin resistance in adipose tissue. (C) 2015 Elsevier B.V. All rights reserved.

引用

页码：1049 / 1058

页数：10

共 47 条

[1] Single nucleotide polymorphisms of PPARD in combination with the Gly482Ser substitution of PGC-1A and the Pro12Ala substitution of PPARG2 predict the conversion from impaired glucose tolerance to type 2 diabetes -: The STOP-NIDDM trial [J].