<i>Caenorhabditis elegans</i> PAQR-2 and IGLR-2 Protect against Glucose Toxicity by Modulating Membrane Lipid Composition

In spite of the worldwide impact of diabetes on human health, the mechanisms behind glucose toxicity remain elusive. Here we show that C. elegans mutants lacking paqr-2, the worm homolog of the adiponectin receptors AdipoR1/2, or its newly identified functional partner iglr-2, are glucose intolerant and die in the presence of as little as 20 mM glucose. Using FRAP (Fluorescence Recovery After Photobleaching) on living worms, we found that cultivation in the presence of glucose causes a decrease in membrane fluidity in paqr-2 and iglr-2 mutants and that genetic suppressors of this sensitivity act to restore membrane fluidity by promoting fatty acid desaturation. The essential roles of paqr-2 and iglr-2 in the presence of glucose are completely independent from daf-2 and daf-16, the C. elegans homologs of the insulin receptor and its downstream target FoxO, respectively. Using bimolecular fluorescence complementation, we also show that PAQR-2 and IGLR-2 interact on plasma membranes and thus may act together as a fluidity sensor that controls membrane lipid composition.尽管糖尿病对人类健康具有全球性影响，但葡萄糖毒性背后的具体机制仍尚未完全阐明。本研究发现，缺失paqr-2（脂联素受体AdipoR1/2在秀丽隐杆线虫中的同源基因）或其新鉴定的功能互作伴侣iglr-2的秀丽隐杆线虫（C. elegans）突变体呈现葡萄糖不耐受表型，且仅需20 mM葡萄糖即可导致其死亡。通过对活线虫进行荧光漂白后恢复（FRAP, Fluorescence Recovery After Photobleaching）实验，本研究观察到，在葡萄糖环境中培养会降低paqr-2与iglr-2突变体的细胞膜流动性，而该敏感性的遗传抑制因子可通过促进脂肪酸去饱和作用恢复细胞膜流动性。paqr-2与iglr-2在葡萄糖环境中的核心功能，完全独立于胰岛素受体及其下游靶标FoxO在秀丽隐杆线虫中的同源基因daf-2与daf-16。借助双分子荧光互补（BiFC, Bimolecular Fluorescence Complementation）实验，本研究还证实PAQR-2与IGLR-2可在细胞膜上相互结合，因此二者可能共同作为流动性传感器，调控细胞膜脂质组成。