Figure 4. Ang-(1-7) promotes thermogenesis, BAT activity, and energy metabolism in the Leprdb/db and the HFD-induced obese mice.
4
Mas1的敲除会损害棕色脂肪组织的产热
ACE2水解产生的Ang-(1-7)通过Mas1受体发挥功能,那么Mas1受体是否决定了Ang-(1-7)在棕色脂肪组织中的作用呢。首先,课题组发现高脂诱导的Mas1-/-小鼠,与对照小鼠相比,表现出糖耐量受损、血脂异常,耗氧量降低(VO2)(图5-图补充1D)。此外,在22°C或4°C下,Mas1-/-小鼠的产热低于WT小鼠(图5C、D、F)。分析表明,Mas1-/-小鼠在BAT中的PET-CT信号低于WT小鼠(图5E)。Mas1的缺失导致BAT产热蛋白(UCP-1、UQCRC2和SDHB)的显著抑制(图5I)。 为了研究Mas1受体在BAT中的作用,课题组构建了BAT特异性Mas1敲除小鼠(Mas1-/-BAT移植小鼠)模型。首先,将野生型C57B/L6受体小鼠的BAT从肩胛间区移除。然后,将品系、性别和年龄匹配的Mas1-/-供体小鼠BAT解剖出来,移植到C57B/L6受体小鼠的背肩胛间区域(WT+Mas1-/--BAT)。作为对照,移植了野生型C57B/L6小鼠BAT(WT+WT-BAT)和C57B/L6小鼠附睾白色脂肪组织(eWAT)(WT+WT-eWAT)的C57B/L6受体小鼠分别用作阳性对照和阴性对照。移植后,受体小鼠用高脂饲料喂养10周。有趣的是,与WT+WT-BAT对照小鼠相比,WT+Mas1-/--BAT小鼠表现出严重受损的胰岛素抵抗。WT+Mas1-/--BAT小鼠和WT+WT-eWAT小鼠在葡萄糖耐量试验(GTT)和胰岛素耐量试验(ITT)中没有显著差异(图5J,K)。值得注意的是,HFD诱导的WT+Mas1-/--BAT小鼠体重显著大于WT+WT-BAT对照小鼠(图5L)。更重要的是,与WT+WT-BAT对照小鼠相比,WT+Mas1-/--BAT小鼠的耗氧量(VO2)和能量消耗(EE)降低(图5M-O)。这些结果表明,Mas1受体可以直接诱导棕色脂肪组织的产热。 Figure 5. Ablation of Mas1 impairs thermogenesis, BAT activity, and energetic metabolism. 5
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