Circulating miR-143-3p inhibition protects against insulin resistance in Metabolic Syndrome via targeting of the insulin-like growth factor 2 receptor

Abstract

Metabolic syndrome (MetS) is characterized by a cluster of metabolic disorders including obesity, dyslipidemia, hyperglycemia, and hypertension. Here, we report that 27 microRNAs were found to be expressed differently in serum and urine samples of MetS patients compared to control subjects on microarray analysis. Further qualitative real time-polymerase chain reaction analyses confirmed that circulating levels of miR-143-3p were significantly elevated in MetS patients compared with controls, both in serum and urine samples. After accounting for confounding factors, high levels of miR-143-3p remained an independent risk factor for insulin resistance. Inhibition of miR-143-3p expression in mice protected against development of obesity-associated insulin resistance. Furthermore, we demonstrated that insulin-like growth factor 2 receptor (IGF2R) was among the target genes of miR-143-3p by searching 3 widely used bioinformatics databases and preliminary validation. Our experiments suggest that knockdown of circulating miR-143-3p may protect against insulin resistance in the setting of MetS via targeting of IGF2R and activation of the insulin signaling pathway. Our results characterize the miR-143-3p-IGF2R pathway as a potential target for the treatment of obesity-associated insulin resistance.

Urinary miRNA‑29a‑3p levels are associated with metabolic parameters via regulation of IGF1 in patients with metabolic syndrome

“…Random numbers were generated electronically and 40 patients with MetS (56.78±6.69 years; 45% male) and 40 control subjects (56.83±6.00 years; 57.5% male) were selected. Baseline anthropometric and metabolic measures were recorded using standardized methods (19,20). Participants were interviewed face-to-face, completing a questionnaire regarding demographic data, life style, present and past illness, medical therapy and other health-associated information.…”

“…Participants were interviewed face-to-face, completing a questionnaire regarding demographic data, life style, present and past illness, medical therapy and other health-associated information. All measurements were referred to as previously reported (19,20). 2 .…”

“…To identify potential molecular targets of miR-29a-3p in patients with MetS, gene ontology and biological association analyses using the Database for Annotation, Visualization and Integrated Discovery Bioinformatics Resources were performed (27) and searched for enrichment of specific target genes associated with insulin signaling, as well as glucose and lipid metabolism. Following evaluation of three widely used bioinformatics databases (20), it was determined that IGF1 was a potential target of miR-29a-3p (Fig. 3A).…”

MiRNAs as Novel Adipokines: Obesity-Related Circulating MiRNAs Influence Chemosensitivity in Cancer Patients

“…A study by Chen and colleagues have attributed these differences to the stage of adipocyte differentiation [162]. A further role has been identified in insulin resistance through targeting of the insulin-like growth factor 2 receptor and subsequent activation of the insulin signaling pathway [163]. The expression of miRNA-143 differs in different tissues, its expression is downregulated in subcutaneous adipose tissue of obese individuals [67], whereas animal models show up-regulation of adipose tissue expression, and also it is increased in the liver, pancreas and circulation [164] making its role in cancer and treatment sensitivity complex.…”

Urine microRNA Profiling Displays miR-125a Dysregulation in Children with Fragile X Syndrome

“…Mounting evidence indicates that miRNAs are involved in the pathophysiology of several disorders, and disease-specific extracellular miRNA profiles have been identified [5]. Changes in circulating miRNAs have been implicated in metabolic crosstalk between organs as well as in neurodegeneration [6,7]. The accessibility and stability of circulating miRNAs support their use as biomarkers for patient stratification to improve the efficacy of targeted treatments [3].…”