title: TWEAK prevents TNF-α-induced insulin resistance through PP2A activation in human adipocytes.
abstract: Visceral fat is strongly associated with insulin resistance. Obesity-associated adipose tissue inflammation and inflammatory cytokine production are considered key mediators of insulin signaling inhibition. TWEAK is a relatively new member of the TNF cytokine superfamily, which can exist as full length membrane-associated (mTWEAK) and soluble (sTWEAK) isoforms. Although TWEAK has been shown to have important functions in chronic inflammatory diseases its physiological role in adipose tissue remains unresolved. In this study, we explore the molecular mechanisms involved in the modulation of TNF-α-induced effects on insulin sensitivity by sTWEAK in a human visceral adipose cell line and also in primary human adipocytes obtained from visceral fat depots. Our data reveal that sTWEAK ameliorates TNF-α-induced insulin resistance on glucose uptake, GLUT4 translocation and insulin signaling without affecting other metabolic effects of TNF-α such as lipolysis or apoptotis. Co-immunoprecipitation experiments in adipose cells revealed that pretreatment with sTWEAK specifically inhibits TRAF2 association with TNFR1, but not with TNFR2, which mediates insulin resistance. However, sTWEAK does not affect other downstream molecules activated by TNF-α, such as TAK1. Rather, sTWEAK abolishes the stimulatory effect of TNF-α on JNK1/2, which is directly involved in the development of insulin resistance. This is associated with an increase in PP2A activity upon sTWEAK treatment. Silencing of the PP2A catalytic subunit gene overcomes the dephosphorylation effect of sTWEAK on JNK1/2, pointing to PP2A as a relevant mediator of sTWEAK-induced JNK inactivation. Overall, our data reveal a protective role of TWEAK in glucose homeostasis and identify PP2A as a new driver in the modulation of TNF-α signaling by sTWEAK.
authors: Department of Biochemistry and Molecular Biology II, School of Pharmacy, Complutense University, Instituto de Investigación Sanitaria del Hospital Clínico San Carlos, Madrid, Spain.
authors: Ana
authors: A
authors: Vázquez-Carballo
authors: Victòria
authors: V
authors: Ceperuelo-Mallafré
authors: Matilde R
authors: MR
authors: Chacón
authors: Elsa
authors: E
authors: Maymó-Masip
authors: Margarita
authors: M
authors: Lorenzo
authors: Almudena
authors: A
authors: Porras
authors: Joan
authors: J
authors: Vendrell
authors: Sonia
authors: S
authors: Fernández-Veledo
mesh_terms: D002460:Cell Line; D000074049:Cytokine TWEAK; D005947:Glucose / Q000378:metabolism; D051275:Glucose Transporter Type 4 / Q000378:metabolism; D006801:Humans; D007333:Insulin Resistance / Q000502:physiology*; D050152:Intra-Abdominal Fat / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism*; D020935:MAP Kinase Signaling System / Q000502:physiology; D009765:Obesity / Q000378:metabolism; D061251:Primary Cell Culture; D054648:Protein Phosphatase 2 / Q000378:metabolism*; D012995:Solubility; D047992:TNF Receptor-Associated Factor 2 / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*; D048069:Tumor Necrosis Factors / Q000378:metabolism*
chemical_list: D000074049:Cytokine TWEAK; D051275:Glucose Transporter Type 4; C495692:SLC2A4 protein, human; D047992:TNF Receptor-Associated Factor 2; C109743:TNFSF12 protein, human; D014409:Tumor Necrosis Factor-alpha; D048069:Tumor Necrosis Factors; C517189:PPP2CA protein, human; D054648:Protein Phosphatase 2; D005947:Glucose
keywords: TNF; adipose tissue; glucose uptake; insulin signaling; obesity; phosphatases