Uninephrectomy and class II PI3K-C2ß inactivation synergistically protect against obesity, insulin resistance and liver steatosis in mice.
Uninephrectomy and class II PI3K-C2ß inactivation synergistically protect against obesity, insulin resistance and liver steatosis in mice.
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单肾切除术和 II 类 PI3K-C2α 灭活可协同保护小鼠免受肥胖、胰岛素抵抗和肝脏脂肪变性。
DOI：
10.1111/ajt.16470
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发表时间：
2021
期刊：
影响因子：
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通讯作者：
Alliouachene S
中科院分区：
文献类型：
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作者：
Alliouachene S
用于移植的活体肾捐献者的单肾切除术（UNx）现已成为常规临床实践。虽然双侧肾功能障碍导致的慢性肾病与胰岛素抵抗、肝脏脂肪变性和 2 型糖尿病有关，但 UNx 的代谢影响仍不清楚。为了更好地了解肾脏和胰岛素靶组织之间的串扰，我们研究了 UNx 的代谢后果以及 II 类 PI3K-C2β 的潜在参与，据报道其失活会导致胰岛素敏化。小鼠接受 UNx 或假手术，然后接受正常饮食或高脂肪饮食 (HFD)。 UNx 后 17 周，小鼠的葡萄糖耐量、胰岛素敏感性得到改善，并且 HFD 诱导的肝脏脂肪变性减少。这与瘦小鼠和肥胖小鼠的肝脏和肌肉中血清 FGF21 和胰岛素刺激的 Akt 信号增强有关。值得注意的是，UNx 和 PI3K-C2β 失活的组合可以防止 HFD 诱导的肥胖，并进一步增强 WT UNx 小鼠中观察到的代谢改善，与代谢组织中 (1) 胰岛素刺激的 Akt 信号传导 (2) FGFR1 和 βKlotho 表达的协同增加相关。我们证明了肾脏捐献的潜在有益作用，以及通过胰岛素/FGF21 相互敏化更有效地灭活 PI3K-C2β 来预防代谢紊乱
Uninephrectomy (UNx) in living kidney donors for transplantation is now routine clinical practice. While chronic kidney disease, due to bilateral kidney dysfunction, is associated with insulin resistance, liver steatosis, and type 2 diabetes, the metabolic impact of UNx remains unclear. To better understand the crosstalk between the kidney and insulin target tissues, we studied the metabolic consequences of UNx and the potential involvement of class II PI3K‐C2β, the inactivation of which has been reported to result in insulin sensitization. Mice underwent UNx or sham operation followed by either normal chow or high‐fat diet (HFD). Seventeen weeks post‐UNx, mice showed improved glucose tolerance, insulin sensitivity, and decreased HFD‐induced liver steatosis. This was associated with an enhanced serum FGF21 and insulin‐stimulated Akt signaling in the liver and muscle of both lean and obese mice. Remarkably, the combination of UNx and PI3K‐C2β inactivation protected against HFD‐induced obesity and further potentiated the metabolic improvement observed in WT UNx mice correlating with a synergistic increase in metabolic tissues of (1) insulin‐stimulated Akt signaling (2) FGFR1 and βKlotho expression. We demonstrated a potential beneficial effect of kidney donation and more effectively with PI3K‐C2β inactivation to protect against metabolic disorders through a mutual insulin/FGF21 sensitization