Conclusions
MicroRNA-203 (miR-203) promotes white adipose tissue browning in cold exposed mice and improves glucose tolerance in HFD fed mice by repressing IFN-γ. Since miR-203 is activated by cAMP-dependent C/EBPβ up-regulation and directly represses IFN-γ signal pathway, we declare that miR-203 acts as a messenger between cAMP signal pathway and IFN-γ signal pathway.
Methods
We investigated the relationship between miR-203 and energy homeostasis in adipose tissue from cold exposed, high fat diet (HFD) fed, ob/ob and db/db mice. The functions of miR-203 on sub-WAT browning were validated through miR-203 knockdown or overexpression. The miR-203 targeted signal pathway was screened by RNAseq analysis. Luciferase report assay, western blot, and qPCR were performed to establish the miR-203 related upstream and downstream signal pathway in vivo and in vitro. The functions of miR-203 on obesity and metabolic homeostasis were validated through GTT/ITT and western blot on high fat diet-induced obesity in C57 mice. ELISA was used to determine the concentration of IFN-γ. Flow cytometry analysis was performed to determine the infiltration of macrophages in adipose tissue.
Objective
Brown and beige adipocytes in humans and rodents are specialized to burn lipids for heat generation as a natural defense against cold and obesity, which is advantageous to metabolic homeostasis. MicroRNAs as another regulatory layer to regulate metabolic homeostasis attracted a lot of attentions. Our previous work revealed microRNA (miR)-203 as a brown adipocyte-enriched microRNA involved in brown adipocytes development. However, the potential role of miR-203 in adipose tissue metabolic homeostasis has not been determined in vivo. In this study, we investigate the potential role of miR-203 in subcutaneous white adipose tissue (sub-WAT) browning and metabolic homeostasis.
Results
MiR-203 expression positively correlates with energy expenditure, and overexpression of miR-203 could enhance sub-WAT browning in normal diet (ND) condition. Mechanistically, the expression of miR-203 is activated by cAMP-dependent C/EBPβ up-regulation. Subsequently, miR-203 inhibits IFN-γ signal pathway activation by directly targeting Lyn, which is an activator of Jak1-Stat1. Moreover, the forced expression of miR-203 could improve insulin sensitivity and resist high fat diet-induced obesity by inhibiting IFN-γ. Conclusions: MicroRNA-203 (miR-203) promotes white adipose tissue browning in cold exposed mice and improves glucose tolerance in HFD fed mice by repressing IFN-γ. Since miR-203 is activated by cAMP-dependent C/EBPβ up-regulation and directly represses IFN-γ signal pathway, we declare that miR-203 acts as a messenger between cAMP signal pathway and IFN-γ signal pathway.