Objective: Up-regulated expression of transcription-factor E2F1 in human visceral adipose
tissue (VAT) characterizes a dysmetabolic obesity sub-phenotype. An E2F1-miRNA network has
been described in multiple cancers. Here we investigated whether elevated VAT-E2F1 in obesity
is associated with VAT-miRNA alterations similar to, or distinct from, those described in cancer.
Furthermore, we assessed if E2F1-associated miRNA changes may contribute to the link between
high- VAT-E2F1 and a dysmetabolic obesity phenotype. Methods: We assembled a cohort of patients
with obesity and high-VAT-E2F1, matched by age, sex, ±BMI to patients with low-VAT-E2F1, with and
without obesity (8 patients/groupX3 groups). We performed Nanostring -based miRNA profiling
of VAT samples from all 24 patients. Candidate E2F1-related miRNAs were validated by qPCR in
an independent cohort of patients with extreme obesity, with or without type-2-diabetes (T2DM)
(n = 20). Bioinformatic tools and manipulation of E2F1 expression in cells were used to establish the
plausibility of the functional VAT-E2F1-miRNA network in obesity. Results: Among n = 798 identified
miRNAs, 17 were differentially expressed in relation to E2F1 and not to obesity itself. No evidence for
the cancer-related E2F1-miRNA network was identified in human VAT in obesity. In HEK293-cells,
overexpression/downregulation of E2F1 correspondingly altered the expression of miRNA-206 and
miRNA-210-5p, two miRNAs with reported metabolic functions consistent with those of E2F1. In
VAT from both cohorts, the expression of both miRNA-206 and 210-5p intercorrelated, and correlated
with the expression of E2F1. In cohort 1 we did not detect significant associations with biochemical
parameters. In cohort 2 of patients with extreme obesity, all those with high VAT-E2F1 showed a
diabetes-complicated obesity phenotype and higher expression of miRNA-206 and miRNA-210-5p,
which also correlated with fasting glucose levels (both miRNAs) and fasting insulin (miRNA-210-5p).
Conclusions: Whilst the previously described cancer-related E2F1-miRNA network does not appear
to operate in VAT in obesity, miRNAs-206 and 210-5p may link high-E2F1 expression in VAT with
diabetes-complicated extreme obesity phenotype.
| Identifer | oai:union.ndltd.org:DRESDEN/oai:qucosa:de:qucosa:90298 |
| Date | 04 March 2024 |
| Creators | Maixner, Nitzan, Haim, Yulia, Blüher, Matthias, Chalifa-Caspi, Vered, Veksler-Lublinsky, Isana, Makarenkov, Nataly, Yoel, Uri, Bashan, Nava, Liberty, Idit F., Kukeev, Ivan, Dukhno, Oleg, Levy, Dan, Rudich, Assaf |
| Publisher | MDPI |
| Source Sets | Hochschulschriftenserver (HSSS) der SLUB Dresden |
| Language | English |
| Detected Language | English |
| Type | info:eu-repo/semantics/publishedVersion, doc-type:article, info:eu-repo/semantics/article, doc-type:Text |
| Rights | info:eu-repo/semantics/openAccess |
| Relation | 3046 |
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