A trail-tl1a paracrine network involving adipocytes, macrophages, and lymphocytes induces adipose tissue dysfunction downstream of e2f1 in human obesity

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

Research output: Contribution to journalArticlepeer-review

5 Scopus citations

Abstract

Elevated expression of E2F1 in adipocyte fraction of human visceral adipose tissue (hVAT) associates with a poor cardiometabolic 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). Tumor necrosis factor superfamily (TNFSF) 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 CD41 and CD81 subclasses of hVAT T cells. In human adipocytes, TL1A enhanced basal and impaired insulin-inhibitable lipolysis and altered adipo-kine secretion, and in human macrophages it induced foam cell 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 TNFSF paracrine loop engaging lympho-cytes, macrophages, and adipocytes, ultimately contributing to adipose tissue dysfunction in obesity.

Original languageEnglish
Pages (from-to)2310-2323
Number of pages14
JournalDiabetes
Volume69
Issue number11
DOIs
StatePublished - 1 Nov 2020

Fingerprint

Dive into the research topics of 'A trail-tl1a paracrine network involving adipocytes, macrophages, and lymphocytes induces adipose tissue dysfunction downstream of e2f1 in human obesity'. Together they form a unique fingerprint.

Cite this