Influence of Obesity in the miRNome: miR-4454, a Key Regulator of Insulin Response Via Splicing Modulation in Prostate

Abstract

Context 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. Objective To explore the differential expression pattern of microRNAs 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/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. Results 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. 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.

Similarities and Differences in Extracellular Vesicle Profiles between Ischaemic Stroke and Myocardial Infarction

“…Four patients per group were selected for the quantitative polymerase chain reaction (PCR) hybridization array screening, as previously described [ 19 ]. These four patients per group were chosen for homogeneous and similar lesions and matched in terms of age and sex.…”

Physical Exercise Mitigates the Disturbs Caused in Ventral Prostate by High Fat Diet, Clarifying the Role of PPAR-Alpha

“…The high-fat diet (HFD, 59% kcal fat) is related to the development of obesity, glucose tolerance, and in ammation. Metabolic alterations related to obesity are strong stimulators of the development of prostate cancer 31 . HFD was e cient to promote an increase in weight gain and the adipose index compared to animals fed a standard diet in WT mice.…”

Interplay of RNA-Binding Proteins and microRNAs in Neurodegenerative Diseases

“…RBM45 forms nuclear and cytoplasmic inclusions in the neurons and glia in AD, as well as ALS and FTLD-TDP, through a persistent association with nuclear stress bodies, thereby promoting its own aggregation into insoluble inclusions [162]. RBM45 acts as a component of the spliceosome, and its splicing process is regulated by miR-4454 in response to insulin signaling in a cell type-dependent manner, although such regulation has been reported only in the prostate glands so far [163]. The direct interaction of tau with TIA1 in the presence of RNA promotes the phase separation of tau and the formation of toxic oligomeric tau [164].…”