BACE1 inhibition via miR-6838-5p overexpression inhibits insulin resistance and the immune response in HFD-induced obesity in mice model.

Han, Yubo; Quan, Zhenhua; Tian, Miao; Wang, Ruinan; Guo, Donghao; Zhang, Dandan; Liu, Li

Context: Obesity is a chronic inflammatory disorder, which promotes the progression of metabolic disorders. MicroRNA (miR)-6838-5p is dysregulated and participates in the progression of several disorder models. Objective: To explore the role and mechanism of miR-6838-5p in insulin resistance. Methods: Mice were fed with high-fat diet (HFD) to construct an obesity animal model. The role of miR-6838-5p was evaluated by insulin tolerance test (ITT), glucose tolerance test (GTT), homeostasis model assessment of insulin resistance (HOMA-IR) analysis, enzyme-linked immunosorbent assay (ELISA) and western blot assays. The potential target of miR-6838-5p was screened through the starBase online website and confirmed by the luciferase assay. Results: HFD supply induced a prominent increase in the body weight, white adipose tissue (WAT) weight, the area under the curve (AUC) of GTT and ITT, HOMA-IR, the serum level of insulin and the serum concentrations and relative protein levels of interleukin (IL)-1β, IL-6 and monocyte chemoattractant protein-1 (MCP-1) accompanied with reduced levels of IL-10 in mice. The level of miR-6838-5p was reduced in HFD-fed mice. Upregulation of miR-6838-5p partly reversed the above-mentioned indicators. Moreover, miR-6838-5p directly targeted to β-site amyloid precursor protein cleaving enzyme1 (BACE1) and negatively regulated the BACE1 expression. Downregulation of BACE1 improved insulin sensitivity and inflammatory mediators release involving in AKT/GSK3β signaling pathway in HFD-fed mice. Besides, overexpression of BACE1 counteracted the depressant role of miR-6838-5p overexpression in insulin resistance and inflammatory factors release in HFD-fed mice. Conclusion: MiR-6838-5p/BACE1 axis regulated insulin resistance and inflammatory factors release in HFD-fed mice.

INSULIN sensitivity; WHITE adipose tissue; INSULIN resistance; ENZYME-linked immunosorbent assay; GLUCOSE tolerance tests

Immunopharmacology & Immunotoxicology, 2025, Vol 47, Issue 1, p42

0892-3973

Academic Journal

10.1080/08923973.2024.2430668