ECE2020 Oral Communications Diabetes, Obesity, Metabolism and Nutrition (7 abstracts)
Influence of obesity in the miRNome landscape: miR-4454, a tissue-specific regulator of insulin response
Prudencio Sáez-Martínez 1,2 , Vicente Herrero-Aguayo 1,2 , Juan M Jiménez-Vacas 1,2 , Juan L López-Cánovas 1,2 , Lourdes Garrido-Sánchez 3 , Manuel Macías-González 3 , José López-Miranda 2,4,5 , Enrique Gómez--Gómez 4,6 , Justo P Castaño-Fuentes 1,2 , Manuel D Gahete-Ortíz 1,2 & Raúl M Luque-Huertas 1,2
1Maimonides Institute of Biomedical Research of Cordoba (IMIBIC), Department of Cell Biology, Physiology and Immunology, University of Cordoba, Córdoba, Spain; 2Carlos III Health Institute, CIBER Physiopathology of Obesity and Nutrition (CIBERobn), Madrid, Spain; 3Biomedical Research Institute of Malaga (IBIMA), Clinical Management and Endocrinology and Nutrition Unit; Hospital (Virgen de la Victoria), University of Malaga, Malaga , Spain; 4Maimonides Institute of Biomedical Research of Cordoba (IMIBIC), Córdoba, Spain; 5Reina Sofia University Hospital, Lipids and Atherosclerosis Unit, Córdoba, Spain; 6Reina Sofia University Hospital, Urology Service, Córdoba, Spain
Obesity is a major health problem commonly associated with severe comorbidities, including insulin resistance and type 2 diabetes mellitus (T2DM). Emerging evidence suggests that production and secretion of certain micro RNAs (miRNAs) are dysregulated under adverse metabolic conditions and might exert a key role in the development and progression of different metabolic-related pathologies. However, the alteration of the plasma miRNA profile under obesity condition and its pathophysiological implication in insulin resistance and T2DM has not been fully explored. Here, we aimed to explore the dysregulations of the miRNome landscape in human obesity and to unveil the putative role/association of key altered miRNAs with basic clinical characteristics in obesity. Specifically, an Affymetrix-miRNA 4.1 array was implemented in a pilot cohort of plasma samples from normoweight and obese patients (BMI < 25 vs >30), and the main changes were further validated in two independent cohorts of patients (n = 221/n = 20). Moreover, different in vitro (using cell models derived from metabolic-tissues) and in silico approaches were performed. Our results demonstrated a profound dysregulation in the human miRNome under obesity conditions. Interestingly, miR-4454 was consistently elevated in plasma of obese patients compared to control patients in all the cohorts, and was positively associated with key clinical parameters related to insulin resistance (i.e. insulin levels, HOMA-IR and HbA1b). We found that miR-4454 is mainly expressed in liver and prostate tissues. Consistent with this, in vitro treatment with high-dose of insulin induced an overexpression of miR-4454 in liver and prostate cell-line models (HEPG2 and RWPE-1, respectively). Moreover, forced overexpression of miR-4454 led to a marked downregulation in the expression of insulin response-related genes (i.e. INSR, IRB, GLUT4) and to a reduction in the activity of key proteins involved in insulin-signaling pathways (i.e. AMPK and AKT). Additionally, miR-4454 overexpression resulted into a clear alteration of several key splicing factors and spliceosome components associated with the development of T2DM (i.e. ESRP1, ESRP2, RBM45 and RNU2). Finally, our data showed that bariatric surgery and the treatment with anti-diabetic/obesity drugs (biguanides or statins) led to a reduction in plasma level of miR-4454, which is consistent with a putative role and implication of miR-4454 in obesity. Altogether, our results suggest that miR-4454 could be considered as a novel diagnostic and/or therapeutic target for obesity and its associated comorbidities such as insulin resistance and T2DM.
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Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
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