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A TRAIL-TL1A paracrine network involving adipocytes, macrophages and lymphocytes induces adipose tissue dysfunction downstream of E2F1 in human obesity

posted on 30.07.2020 by Ada Admin, Nitzan Maixner, Tal Pecht, Yulia Haim, Vered Chalifa-Caspi, Nir Goldstein, Tania Tarnovscki, Idit F. Liberty, Boris Kirshtein, Rachel Golan, Omer Berner, Alon Monsonego, Nava Bashan, Matthias Blüher, Assaf Rudich
Elevated expression of E2F1 in adipocyte-fraction of human visceral adipose-tissue(hVAT) associates with a poor cardio-metabolic profile. We hypothesized that beyond directly activating autophagy and MAP3K5(ASK)-MAP-kinase signaling, E2F1 governs a distinct transcriptome that contributes to adipose-tissue and metabolic dysfunction in obesity. We performed RNA-sequencing of hVAT samples from age-, sex- and BMI–matched patients, all obese, whose visceral-E2F1 protein expression was either high(E2F1high) or low(E2F1low). TNF-superfamily members, including TRAIL(TNFSF10), TL1A(TNFSF15) and their receptors were enriched in E2F1high. While TRAIL was equally expressed in adipocytes and stromal-vascular fraction(SVF), TL1A was mainly expressed in SVF, and TRAIL-induced TL1A was attributed to CD4+ and CD8+-subclasses of hVAT T-lymphocytes. In human adipocytes TL1A enhanced basal and impaired insulin-inhibitable lipolysis, and altered adipokine secretion, and in human macrophages induced foam-cells biogenesis and M1-polarization. Two independent human cohorts confirmed associations between TL1A and TRAIL expression in hVAT and higher leptin and IL6 serum concentrations, diabetes status, and hVAT-macrophage lipid content. Jointly, we propose an intra-adipose tissue E2F1-associated TNF-superfamily paracrine loop engaging lymphocytes, macrophages and adipocytes, ultimately contributing to adipose-tissue dysfunction in obesity.


This study was supported in part by grants from the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) 209933838: SFB1052:“Obesity mechanisms”, and the Israel Science Foundation (ISF 2176/19).