miR-210 in Exosomes Derived from Macrophages under High Glucose Promotes Mouse Diabetic Obesity Pathogenesis by Suppressing NDUFA4 Expression

Abstract

Objective. Type 2 diabetes mellitus (T2DM) is featured by insulin resistance and lipid metabolism dysregulation. A large number of miRNAs were identified in exosomes derived from adipose tissue macrophages associated with T2DM pathogenesis, but its pathogenic roles remain unknown. This study is aimed at investigating the function of miR-210 in diabetic obesity. Methods. Exosomes from mouse macrophage RAW264.7 cells were characterized by electron microscopy, combined with biomarker expression by western blot. Expression of miR-210 was determined by quantitative RT-PCR. Glucose uptake was measured by a fluorometric method, and the mitochondrial respiratory chain activity was evaluated by ELISA. The target gene of miR-210 was validated by dual-luciferase reporter and pull-down assays. A mouse obese diabetic model was established by a high-fat diet and streptozocin treatment. Results. miR-210 was highly expressed in exosomes derived from high glucose-induced macrophage RAW264.7 cells. Macrophage-derived exosomes impaired glucose uptake and mitochondrial CIV complex activity and suppressed NADH dehydrogenase ubiquinone 1 alpha subcomplex 4 (NDUFA4) expression in 3T3-L1 adipocytes. miR-210 directly bind with mRNA sequences of NDUFA4 gene. Inhibition of miR-210 mitigated the effects of macrophage-derived exosomes on the glucose uptake and complex IV (CIV) activity in 3T3-L1 adipocytes, and NDUFA4 overexpression offset the inhibition of glucose uptake and CIV activity by macrophage-derived exosomes. Furthermore, mice with miR-210 knockout showed greatly repressed diabetic obesity development. Conclusion. miR-210 derived from adipose tissue macrophages promotes mouse obese diabetes pathogenesis by regulating glucose uptake and mitochondrial CIV activity through targeting NDUFA4 gene expression.

Macrophage miR-210 induction and metabolic reprogramming in response to pathogen interaction boost life-threatening inflammation

“…MiR-210 was detectable in the extracellular milieu of LPS-stimulated murine or human macrophages and in the plasma of both septic mice and patients. Released miR-210, free or in exosomes, might regulate (metabolic) gene expression of neighboring cells as shown, for miR-210 (40) and other miRs (8,63,64) in different contexts.…”

“…on June 6, 2021 http://advances.sciencemag.org/ Downloaded from Soluble markers of sepsis are so far missing. It has been recently demonstrated that miR-210 can be found in the exosomes of a transformed cell line of macrophage origin (40). Therefore, we checked whether the levels of miR-210 in the medium mirrored its expression in macrophages.…”

Potential Roles of Adipocyte Extracellular Vesicle–Derived miRNAs in Obesity-Mediated Insulin Resistance

“…Recently, Tian et al ( 69 ) demonstrated that exosomal miR-210 from high-glucose–induced macrophages inhibited NADH dehydrogenase (ubiquinone) 1ɑ subcomplex 4 (NDUFA4) expression and induced the suppression of glucose uptake in adipocytes. NDUFA4 is one of the subunits of mitochondrial respiratory chain complex IV, and thus it is involved in mitochondrial function ( 70 ).…”

MicroRNAs: The Link between the Metabolic Syndrome and Oncogenesis

“…In patients suffering from obesity, mir-210 is overexpressed in ATM [283]. Moreover, miR-210 resulted from ATM is implicated in the pathogenesis of diabetes in obese mouse models by altering glucose uptake and mitochondrial complex IV activity by targeting NADH dehydrogenase ubiquinone 1 alpha subcomplex 4 gene [308].…”