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Influence of obesity in the miRNome: miR-4454, a key regulator of insulin response via splicing modulation in prostate.

Authors
  • Herrero-Aguayo, Vicente1, 2, 3, 4
  • Jiménez-Vacas, Juan M1, 2, 3, 4
  • Sáez-Martínez, Prudencio1, 2, 3, 4
  • Gómez-Gómez, Enrique1, 3, 5
  • López-Cánovas, Juan L1, 2, 3, 4
  • Garrido-Sánchez, Lourdes4, 6
  • Herrera-Martínez, Aura D1, 3, 7
  • García-Bermejo, Laura8
  • Macías-González, Manuel4, 6
  • López-Miranda, José1, 3, 9
  • Castaño, Justo P1, 2, 3, 4
  • Gahete, Manuel D1, 2, 3, 4
  • Luque, Raúl M1, 2, 3, 4
  • 1 Maimonides Institute for Biomedical Research of Córdoba (IMIBIC), Córdoba, Spain. , (Spain)
  • 2 Department of Cell Biology, Physiology, and Immunology, University of Córdoba, Córdoba, Spain. , (Spain)
  • 3 Hospital Universitario Reina Sofía (HURS), Córdoba, Spain. , (Spain)
  • 4 Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y Nutrición, (CIBERobn), Madrid, Spain. , (Spain)
  • 5 Urology Service, HURS/IMIBIC, Córdoba, Spain. , (Spain)
  • 6 Unidad de Gestión Clínica y Endocrinología y Nutrición, Instituto de Investigación Biomédica de Málaga (IBIMA), Complejo Hospitalario de Málaga (Virgen de la Victoria), Universidad de Málaga, Málaga, Spain. , (Spain)
  • 7 Service of Endocrinology and Nutrition, Córdoba, Spain. , (Spain)
  • 8 Biomarkers and Therapeutic Targets Group-IRYCIS, Madrid, Spain. , (Spain)
  • 9 Lipids and Atherosclerosis Unit, Reina Sofia University Hospital, Córdoba, Spain. , (Spain)
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]

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