Ablation of ORMDL3 impairs adipose tissue thermogenesis and insulin sensitivity by increasing ceramide generation.
Ablation of ORMDL3 impairs adipose tissue thermogenesis and insulin sensitivity by increasing ceramide generation.
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DOI：
10.1016/j.molmet.2021.101423
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发表时间：
2022-03
影响因子：
8.1
通讯作者：
Li P
中科院分区：
文献类型：
--
作者：
Song Y;Zan W;Qin L;Han S;Ye L;Wang M;Jiang B;Fang P;Liu Q;Shao C;Gong Y;Li P
全基因组关联研究发现ORMDL 3为肥胖相关基因，其表达与体重指数呈负相关。然而，ORMDL 3在肥胖和脂质代谢中的精确生物学作用仍然没有表征。在此，我们研究ORMDL 3在脂肪组织产热和高脂饮食（HFD）诱导的胰岛素抵抗中的功能。采用Ormdl 3缺陷（Ormdl 3-/-）小鼠来描述ORMDL 3在棕色脂肪组织（BAT）产热和白色脂肪组织（WAT）布朗宁中的功能。评估了喂食HFD的Ormdl 3 −/−小鼠的葡萄糖和脂质稳态。通过质谱法评价脂肪组织中的脂质组成。培养的原代脂肪细胞用于确定ORMDL 3调节白色脂肪布朗宁的机制。在寒冷暴露或给予β3肾上腺素能激动剂后，Ormdl 3 −/−小鼠的BAT产热和WAT布朗宁显著受损。此外，与WT小鼠相比，Ormdl 3 −/−小鼠对HFD的反应表现出增加的体重增加和胰岛素抵抗。解偶联蛋白1（UCP 1）的诱导，产热的标志物，在来自Ormdl 3 −/−小鼠的原代脂肪细胞中减弱。重要的是，Ormdl 3 −/−小鼠脂肪组织中的神经酰胺水平升高。此外，Ormdl 3缺乏引起的产热减少和体重增加可以通过抑制神经酰胺的产生来挽救。我们的研究结果表明，ORMDL 3有助于调节BAT产热，WAT布朗宁和胰岛素抵抗。ORMDL 3在肥胖小鼠和人类的WAT中下调，并在冷暴露中上调。小鼠中Ormdl 3的缺失加剧了由HFD诱导的肥胖引起的总体代谢表型。Ormdl 3消融损害BAT产热和WAT布朗宁。ormdl 3缺乏足以负调节神经酰胺水平。
Genome-wide association studies identified ORMDL3 as an obesity-related gene, and its expression was negatively correlated with body mass index. However, the precise biological roles of ORMDL3 in obesity and lipid metabolism remain uncharacterized. Here, we investigate the function of ORMDL3 in adipose tissue thermogenesis and high fat diet (HFD)-induced insulin resistance. Ormdl3-deficient (Ormdl3−/−) mice were employed to delineate the function of ORMDL3 in brown adipose tissue (BAT) thermogenesis and white adipose tissue (WAT) browning. Glucose and lipid homeostasis in Ormdl3−/− mice fed a HFD were assessed. The lipid composition in adipose tissue was evaluated by mass spectrometry. Primary adipocytes in culture were used to determine the mechanism by which ORMDL3 regulates white adipose browning. BAT thermogenesis and WAT browning were significantly impaired in Ormdl3−/− mice upon cold exposure or administration with the β3 adrenergic agonist. In addition, compared to WT mice, Ormdl3−/− mice displayed increased weight gain and insulin resistance in response to HFD. The induction of uncoupling protein 1 (UCP1), a marker of thermogenesis, was attenuated in primary adipocytes derived from Ormdl3−/− mice. Importantly, ceramide levels were elevated in the adipose tissue of Ormdl3−/− mice. In addition, the reduction in thermogenesis and increase in body weight caused by Ormdl3 deficiency could be rescued by inhibiting the production of ceramides. Our findings suggest that ORMDL3 contributes to the regulation of BAT thermogenesis, WAT browning, and insulin resistance. ORMDL3 is downregulated in WAT of obese mice and humans and upregulated in response to cold exposure. Loss of Ormdl3 in mice exacerbates the overall metabolic phenotypes caused by HFD-induced obesity. Ormdl3 ablation impairs BAT thermogenesis and WAT browning. Ormdl3 deficiency is sufficient for negatively regulating ceramide levels.
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影响因子：
29
作者：
Kajimura S;Spiegelman BM;Seale P
通讯作者：
Seale P
影响因子：
30.8
作者：
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--
影响因子：
64.5
作者：
Fedorenko A;Lishko PV;Kirichok Y
通讯作者：
Kirichok Y
影响因子：
16.8
作者：
Li, Sisi;Xie, Tian;Gong, Xin
通讯作者：
Gong, Xin
ORMDL3 通过 ATF6 α-内质网应激-Beclin1 自噬调节途径促进脾 B 细胞的存活
影响因子：
4.4
作者：
Dang, Jie;Bian, Xianli;Liu, Qiji
通讯作者：
Liu, Qiji