MiR-125b-2 knockout increases high-fat diet-induced fat accumulation and insulin resistance

Abstract

Obese individuals are more susceptible to comorbidities than individuals of healthy weight, including cardiovascular disease and metabolic disorders. MicroRNAs are a class of small and noncoding RNAs that are implicated in the regulation of chronic human diseases. We previously reported that miR-125b plays a critical role in adipogenesis in vitro. However, the involvement of miR-125b-2 in fat metabolism in vivo remains unknown. In the present study, miR-125b-2 knockout mice were generated using CRISPR/CAS9 technology, resulting in mice with a 7 bp deletion in the seed sequence of miR-125b-2. MiR-125b-2 knockout increased the weight of liver tissue, epididymal white fat and inguinal white fat. MiR-125b-2 knockout also increased adipocyte volume in HFD-induced obese mice, while there were no significant differences in body weight and feed intake versus mice fed a normal diet. Additionally, qRT-PCR and western blot analysis revealed that the expression of the miR-125b-2 target gene SCD-1 and fat synthesis-associated genes, such as PPARγ and C/EBPα, were significantly up-regulated in miR-125b-2KO mice (P < 0.05). Moreover, miR-125b-2KO altered HFD-induced changes in glucose tolerance and insulin resistance. In conclusion, we show that miR-125b-2 is a novel potential target for regulating fat accumulation, and also a candidate target to develop novel treatment strategies for obesity and diabetes.

Glucose-dependent miR-125b is a negative regulator of β-cell function

“…These animals were hyperglycaemic and strongly glucose intolerant and presented a drastic reduction in circulating insulin following a glucose challenge. In a paper published during the preparation of this manuscript, Wei and colleagues 40 showed that whole-body MIR125B-2 knockout mice on a high-fat diet, but not on a normal diet, develop insulin resistance and glucose intolerance possibly due to the accumulation of epididymal and inguinal white fat. Consequently, these authors suggest the systemic delivery of miR-125b mimics to intervene obesity-related diseases.…”

“…In summary, our results suggest that β-cell miR-125b has the potential to act as a glucose-regulated metabolic switch between the lysosomal system and mitochondria dynamics. Whole-body MIR125B-2 knockout mice on a high-fat diet develop insulin resistance and glucose intolerance possibly due to the white fat accumulation (48). Nevertheless, insulin secretion or an effect in other metabolic organs were not assessed and our study provides compelling evidence of a role for miR-125b in controlling insulin secretion and strongly indicates that non-targeted administration of miR-125b mimics may reach the islet and lead to defective β-cell function and worsen diabetes.…”

Dietary carbohydrates: Pathogenesis and potential therapeutic targets to obesity‐associated metabolic syndrome

“…Some circulating miRNAs (miRs 34a, 93, 122, 125b‐2, and 192) were significantly associated with prediabetes (IGT) and NAFLD. For example, higher miRNA 192 in obese individuals is directly related to dyslipidemia and liver impairment, 233 while the knockout of miR‐125b‐2 enhanced fat accumulation, IR, and liver weight 234 . Thus, miRNAs may at least be considered as potential metabolic disease biomarkers and miRs based therapeutic approach would be an attractive treatment regimen for reversing MetS and its related complications…”

Differences in liver microRNA profiling in pigs with low and high feed efficiency

“…The miR-24 has been identified to be upregulated in liver of High-FE pigs, and knockdown of miR-24 results in the reduced hepatic lipid accumulation and the decreased plasma triglycerides [71]. In addition, miR-125b, miR-185, and miR-26a have been reported to participate in the lipid accumulation in liver [72][73][74][75].…”