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

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(E2F1^high) or low(E2F1^low). TNF-superfamily members, including TRAIL(TNFSF10), TL1A(TNFSF15) and their receptors were enriched in E2F1^high. 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.