Vicente Herrero-Aguayo1,2,3,4, Juan M Jiménez-Vacas1,2,3,4, Prudencio Sáez-Martínez1,2,3,4, Enrique Gómez-Gómez1,3,5, Juan L López-Cánovas1,2,3,4, Lourdes Garrido-Sánchez4,6, Aura D Herrera-Martínez1,3,7, Laura García-Bermejo8, Manuel Macías-González4,6, José López-Miranda1,3,9, Justo P Castaño1,2,3,4, Manuel D Gahete1,2,3,4, Raúl M Luque1,2,3,4. 1. Maimonides Institute for Biomedical Research of Córdoba (IMIBIC), Córdoba, Spain. 2. Department of Cell Biology, Physiology, and Immunology, University of Córdoba, Córdoba, Spain. 3. Hospital Universitario Reina Sofía (HURS), Córdoba, Spain. 4. Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y Nutrición (CIBERobn), Madrid, Spain. 5. Urology Service, HURS/IMIBIC, Córdoba, 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. 7. Service of Endocrinology and Nutrition, Córdoba, Spain. 8. Biomarkers and Therapeutic Targets Group-IRYCIS, Madrid, Spain. 9. Lipids and Atherosclerosis Unit, Reina Sofia University Hospital, Córdoba, Spain.
Abstract
CONTEXT: Obesity is a major health problem associated with severe comorbidities, including type 2 diabetes and cancer, wherein microRNAs (miRNAs) might be useful as diagnostic/prognostic tools or therapeutic targets. OBJECTIVE: To explore the differential expression pattern of miRNAs in obesity and their putative role in obesity-related comorbidities such as insulin resistance. METHODS: An Affymetrix-miRNA array was performed in plasma samples from normoweight (n = 4/body mass index < 25) and obese subjects (n = 4/body mass index > 30). The main changes were validated in 2 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. RESULTS: A total of 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 (Homeostatic Model Assessment of Insulin Resistance/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. CONCLUSIONS: 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.
CONTEXT: Obesity is a major health problem associated with severe comorbidities, including type 2 diabetes and cancer, wherein microRNAs (miRNAs) might be useful as diagnostic/prognostic tools or therapeutic targets. OBJECTIVE: To explore the differential expression pattern of miRNAs in obesity and their putative role in obesity-related comorbidities such as insulin resistance. METHODS: An Affymetrix-miRNA array was performed in plasma samples from normoweight (n = 4/body mass index < 25) and obese subjects (n = 4/body mass index > 30). The main changes were validated in 2 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. RESULTS: A total of 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 (Homeostatic Model Assessment of Insulin Resistance/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. CONCLUSIONS: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.
Authors: Laura Otero-Ortega; Elisa Alonso-López; María Pérez-Mato; Fernando Laso-García; Mari Carmen Gómez-de Frutos; Luke Diekhorst; María Laura García-Bermejo; Elisa Conde-Moreno; Blanca Fuentes; María Alonso de Leciñana; Eduardo Armada; Lorena Buiza-Palomino; Exuperio Díez-Tejedor; María Gutiérrez-Fernández Journal: Biomedicines Date: 2020-12-24
Authors: Soraya León-Idougourram; Jesús M Pérez-Gómez; Concepción Muñoz Jiménez; Fernando L-López; Gregorio Manzano García; María José Molina Puertas; Natalia Herman-Sánchez; Rosario Alonso-Echague; Alfonso Calañas Continente; María Ángeles Gálvez Moreno; Raúl M Luque; Manuel D Gahete; Aura D Herrera-Martínez Journal: Cancers (Basel) Date: 2022-01-19 Impact factor: 6.639
Authors: Vicente Herrero-Aguayo; Prudencio Sáez-Martínez; Juan M Jiménez-Vacas; M Trinidad Moreno-Montilla; Antonio J Montero-Hidalgo; Jesús M Pérez-Gómez; Juan L López-Canovas; Francisco Porcel-Pastrana; Julia Carrasco-Valiente; Francisco J Anglada; Enrique Gómez-Gómez; Elena M Yubero-Serrano; Alejandro Ibañez-Costa; Aura D Herrera-Martínez; André Sarmento-Cabral; Manuel D Gahete; Raúl M Luque Journal: Mol Ther Nucleic Acids Date: 2022-02-12 Impact factor: 8.886