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PGE2-EP3 axis promotes brown adipose tissue formation through stabilization of WTAP RNA methyltransferase
The EMBO Journal ( IF 9.4 ) Pub Date : 2022-07-04 , DOI: 10.15252/embj.2021110439
Xixi Tao 1 , Ronglu Du 1 , Shumin Guo 1 , Xiangling Feng 1 , Tingting Yu 1 , Qian OuYang 2 , Qiaoli Chen 2 , Xutong Fan 1 , Xueqi Wang 1 , Chen Guo 3 , Xiaozhou Li 3 , Fengxia Xue 3 , Shuai Chen 2 , Minghan Tong 4 , Michael Lazarus 5 , Shengkai Zuo 1 , Ying Yu 1 , Yujun Shen 1
Affiliation  

Brown adipose tissue (BAT) functions as a thermogenic organ and is negatively associated with cardiometabolic diseases. N6-methyladenosine (m6A) modulation regulates the fate of stem cells. Here, we show that the prostaglandin E2 (PGE2)–E-prostanoid receptor 3 (EP3) axis was activated during mouse interscapular BAT development. Disruption of EP3 impaired the browning process during adipocyte differentiation from pre-adipocytes. Brown adipocyte-specific depletion of EP3 compromised interscapular BAT formation and aggravated high-fat diet-induced obesity and insulin resistance in vivo. Mechanistically, activation of EP3 stabilized the Zfp410 mRNA via WTAP-mediated m6A modification, while knockdown of Zfp410 abolished the EP3-induced enhancement of brown adipogenesis. EP3 prevented ubiquitin-mediated degradation of WTAP by eliminating PKA-mediated ERK1/2 inhibition during brown adipocyte differentiation. Ablation of WTAP in brown adipocytes abrogated the protective effect of EP3 overexpression in high-fat diet-fed mice. Inhibition of EP3 also retarded human embryonic stem cell differentiation into mature brown adipocytes by reducing the WTAP levels. Thus, a conserved PGE2-EP3 axis promotes BAT development by stabilizing WTAP/Zfp410 signaling in a PKA/ERK1/2-dependent manner.

中文翻译:

PGE2-EP3 轴通过稳定 WTAP RNA 甲基转移酶促进棕色脂肪组织形成

棕色脂肪组织(BAT)作为产热器官发挥作用,与心脏代谢疾病呈负相关。N 6 -甲基腺苷 (m 6 A) 调节可调节干细胞的命运。在这里,我们发现前列腺素 E 2 (PGE 2 )–E-前列腺素受体 3 (EP3) 轴在小鼠肩胛间 BAT 发育过程中被激活。EP3 的破坏会损害脂肪细胞从前脂肪细胞分化过程中的褐变过程。棕色脂肪细胞特异性去除 EP3 会损害肩胛间 BAT 的形成,并加剧高脂肪饮食诱导的肥胖和体内胰岛素抵抗。从机制上讲,EP3 的激活通过 WTAP 介导的 m 6稳定 Zfp410 mRNA一种修饰,同时敲低 Zfp410 消除了 EP3 诱导的棕色脂肪生成的增强。EP3 通过消除棕色脂肪细胞分化过程中 PKA 介导的 ERK1/2 抑制来阻止泛素介导的 WTAP 降解。棕色脂肪细胞中 WTAP 的消除消除了 EP3 过度表达对高脂肪饮食喂养小鼠的保护作用。抑制 EP3 还可以通过降低 WTAP 水平来延迟人胚胎干细胞分化为成熟的棕色脂肪细胞。因此,保守的 PGE 2 -EP3 轴通过以 PKA/ERK1/2 依赖性方式稳定 WTAP/Zfp410 信号传导来促进 BAT 发育。
更新日期:2022-07-04
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