Loss of miR-23b/27b/24-1 Cluster Impairs Glucose Tolerance via Glycolysis Pathway in Mice.

Yong-Hui Jiang,Han Zhao,Jia-Lin Li,Shi-Gang Zhao,Yue Liu,Huang-Cong Shi,Yuan-Yuan Man,Chang-Jian Yin

doi:10.3390/ijms22020550

Yong-Hui Jiang, Han Zhao + Show 6 more

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https://doi.org/10.3390/ijms22020550

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Abstract

Alterations in miRNAs are associated with many metabolic disorders, such as type 2 diabetes (T2DM). The miR-23b/27b/24-1 cluster contains miR-23b, miR-27b, and miR-24-1, which are located within 881 bp on chromosome 9. Studies examining the roles of miR-23b, miR-27b, and miR-24-1 have demonstrated their multifaceted functions in variable metabolic disorders. However, their joint roles in metabolism in vivo remain elusive. To investigate this subject, we constructed miR-23b/27b/24-1 cluster knockout (KO) mice. Compared with wild-type (WT) mice, the KO mice exhibited impaired glucose tolerance, which was accompanied by a reduction in the respiratory exchange rate (RER). These alterations were more noticeable after a high-fat diet (HFD) induction. Hepatic metabolomic results showed decreased expression of reduced nicotinamide adenine dinucleotide (NADH), nicotinamide adenine dinucleotide (NAD), phosphoenolpyruvic acid (PEP), and phosphoric acid, which are involved in the glycolysis pathway. The transcriptomic results indicated that genes involved in glycolysis showed a downregulation trend. qPCR and Western blot revealed that pyruvate kinase (PKLR), the key rate-limiting enzyme in glycolysis, was significantly reduced after the deletion of the miR-23b/27b/24-1 cluster. Together, these observations suggest that the miR-23b/27b/24-1 cluster is involved in the regulation of glucose homeostasis via the glycolysis pathway.

Highlights

Type 2 diabetes mellitus (T2DM) has increasingly grown to epidemic proportions over the last 30 years
Glucose tolerance was impaired after the ablation of the miR-23b/27b/24-1 cluster, but there was no significant difference in insulin tolerance tests (ITT) and glucose-stimulated insulin secretion (GSIS)
The results showed that knockout of the miR-23b/27b/24-1 cluster in vivo impaired glucose tolerance

Summary

Introduction

Type 2 diabetes mellitus (T2DM) has increasingly grown to epidemic proportions over the last 30 years. MicroRNAs (miRNAs) are involved in the pathogenesis of complex diseases, including T2DM [3,4]. MiR-27b can negatively regulate human adipocyte differentiation by targeting LPL or PPAR-γ genes [13,14]. Both miR-27b and miR-24 levels were decreased in the urine extracellular vesicles of patients with diabetic nephropathy [15]. Other studies have shown that the expression of miR-24 was reduced in T2DM patients [20,21,22]. Elevated expression of all three miRNAs has been reported in the liver of high-fat diet (HFD) mice, and knockdown (KD) of miR-24 caused impaired hepatic lipid accumulation [23,24]. The function of these three miRNAs together in glucose metabolism remains elusive

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