Influence of obesity in the miRNome: miR-4454, a key regulator of insulin response via splicing modulation in prostate.
- Authors
- Type
- Published Article
- Journal
- The Journal of Clinical Endocrinology & Metabolism
- Publisher
- The Endocrine Society
- Publication Date
- Aug 25, 2020
- Identifiers
- DOI: 10.1210/clinem/dgaa580
- PMID: 32841353
- Source
- Medline
- Keywords
- Language
- English
- License
- Unknown
Abstract
Obesity is a major health problem associated with severe comorbidities, including type-2 diabetes and cancer, wherein microRNAs might be useful as diagnostic/prognostic tools or therapeutic targets. To explore the differential expression pattern of microRNAs in obesity and their putative role in obesity-related comorbidities such as insulin resistance. An Affymetrix-miRNA array was performed in plasma samples from normoweight (n=4/BMI&25) and obese subjects (n=4/BMI>30). The main changes were validated in two independent cohorts (n=221/n=18). Additionally, in silico approaches were performed and in vitro assays applied in tissue samples and prostate (RWPE-1) and liver (HepG2) cell-lines. 26 microRNAs were altered (p&0.01) in plasma of obese subjects compared to controls using the Affymetrix-miRNA array. Validation in ampler cohorts revealed that miR-4454 levels were consistently higher in obesity, associated with insulin-resistance (HOMA-IR/insulin) and modulated by medical (metformin/statins) and surgical (bariatric surgery) strategies. miR-4454 was highly expressed in prostate and liver tissues and its expression was increased in prostate and liver cells by insulin. In vitro, overexpression of miR-4454 in prostate cells resulted in decreased expression levels of INSR, GLUT4, and phosphorylation of AMPK/AKT/ERK, as well as in altered expression of key spliceosome components (ESRP1/ESRP2/RBM45/RNU2) and insulin-receptor splicing variants. Obesity was associated to an alteration of the plasmatic miRNA landscape, wherein miR-4454 levels were higher, associated with insulin-resistance and modulated by obesity-controlling interventions. Insulin regulated miR-4454, which, in turn may impair the cellular response to insulin, in a cell type-dependent manner (i.e. prostate gland), by modulating the splicing process. © Endocrine Society 2020. All rights reserved. For permissions, please e-mail: [email protected]
