Biology Science Institutes, Chongqing Medical University, PR China.
Biology Science Institutes, Chongqing Medical University, PR China; Cardiovascular and Metabolic Disorders Program, Duke-NUS Medical School, Singapore.
Mol Metab. 2019 Oct;28:36-47. doi: 10.1016/j.molmet.2019.07.002. Epub 2019 Jul 6.
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.
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.
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.
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.
棕色和米色脂肪细胞在人类和啮齿动物中专门用于燃烧脂质以产生热量，作为对抗寒冷和肥胖的天然防御，这有利于代谢稳态。作为另一个调节代谢稳态的调节层，microRNAs 引起了广泛关注。我们之前的工作表明，microRNA（miR）-203 是一种富含棕色脂肪细胞的 microRNA，参与棕色脂肪细胞的发育。然而，miR-203 在体内脂肪组织代谢稳态中的潜在作用尚未确定。在这项研究中，我们研究了 miR-203 在皮下白色脂肪组织（sub-WAT）褐变和代谢稳态中的潜在作用。
我们研究了 miR-203 与冷暴露、高脂肪饮食（HFD）喂养、ob/ob 和 db/db 小鼠脂肪组织中能量平衡之间的关系。通过 miR-203 敲低或过表达验证了 miR-203 对 sub-WAT 褐变的功能。通过 RNAseq 分析筛选 miR-203 的靶向信号通路。通过荧光素酶报告分析、western blot 和 qPCR 在体内和体外建立了 miR-203 相关的上游和下游信号通路。通过 C57 小鼠高脂肪饮食诱导肥胖的 GTT/ITT 和 western blot 验证了 miR-203 对肥胖和代谢稳态的功能。通过 ELISA 测定 IFN-γ 的浓度。通过流式细胞术分析测定脂肪组织中巨噬细胞的浸润。
miR-203 的表达与能量消耗呈正相关，过表达 miR-203 可增强正常饮食（ND）条件下 sub-WAT 的褐变。在机制上，miR-203 的表达被 cAMP 依赖性 C/EBPβ 的上调所激活。随后，miR-203 通过直接靶向 Lyn 抑制 IFN-γ 信号通路的激活，Lyn 是 Jak1-Stat1 的激活剂。此外，通过抑制 IFN-γ，强制表达 miR-203 可以改善胰岛素敏感性并抵抗高脂肪饮食诱导的肥胖。
microRNA-203（miR-203）通过抑制 IFN-γ 促进冷暴露小鼠白色脂肪组织褐变，并改善高脂肪饮食喂养小鼠的葡萄糖耐量。由于 miR-203 是由 cAMP 依赖性 C/EBPβ 的上调激活的，并且直接抑制 IFN-γ 信号通路，我们宣布 miR-203 充当 cAMP 信号通路和 IFN-γ 信号通路之间的信使。
