Abstract：
OBJECTIVE: To investigate the effect of G protein-coupled receptor 55 (GPR55) deletion on glucose homeostasis and islet function following diet-induced obesity.
METHODS: GPR55-/- and wild-type (WT) mice were fed ad libitum either standard chow (SC) or a high-fat diet (HFD) for 20 weeks. Glucose and insulin tolerance tests were performed at 9/10 and 19/20 weeks of dietary intervention. Insulin secretion in vivo and dynamic insulin secretion following perifusion of isolated islets were also determined, as were islet caspase-3/7 activities and β-cell 5-bromo-20-deoxyuridine (BrdU) incorporation.
RESULTS: GPR55-/- mice fed a HFD were more susceptible to diet-induced obesity and were more glucose intolerant and insulin resistant than WT mice maintained on a HFD. Islets isolated from HFD-fed GPR55-/- mice showed impaired glucose- and pcacahorbol 12-myristate 13-acetate-stimulated insulin secretion, and they also displayed increased cytokine-induced apoptosis. While there was a 5.6 ± 1.6-fold increase in β-cell BrdU incorporation in the pancreases of WT mice fed a HFD, this compensatory increase in β-cell proliferation in response to the HFD was attenuated in GPR55-/- mice.
CONCLUSIONS: Under conditions of diet-induced obesity, GPR55-/- mice show impaired glucose handling, which is associated with reduced insulin secretory capacity, increased islet cell apoptosis and insufficient compensatory increases in β-cell proliferation. These observations support that GPR55 plays an important role in positively regulating islet function.
METHODS: GPR55-/- and wild-type (WT) mice were fed ad libitum either standard chow (SC) or a high-fat diet (HFD) for 20 weeks. Glucose and insulin tolerance tests were performed at 9/10 and 19/20 weeks of dietary intervention. Insulin secretion in vivo and dynamic insulin secretion following perifusion of isolated islets were also determined, as were islet caspase-3/7 activities and β-cell 5-bromo-20-deoxyuridine (BrdU) incorporation.
RESULTS: GPR55-/- mice fed a HFD were more susceptible to diet-induced obesity and were more glucose intolerant and insulin resistant than WT mice maintained on a HFD. Islets isolated from HFD-fed GPR55-/- mice showed impaired glucose- and pcacahorbol 12-myristate 13-acetate-stimulated insulin secretion, and they also displayed increased cytokine-induced apoptosis. While there was a 5.6 ± 1.6-fold increase in β-cell BrdU incorporation in the pancreases of WT mice fed a HFD, this compensatory increase in β-cell proliferation in response to the HFD was attenuated in GPR55-/- mice.
CONCLUSIONS: Under conditions of diet-induced obesity, GPR55-/- mice show impaired glucose handling, which is associated with reduced insulin secretory capacity, increased islet cell apoptosis and insufficient compensatory increases in β-cell proliferation. These observations support that GPR55 plays an important role in positively regulating islet function.
摘要：
目的：探讨G蛋白偶联受体55(GPR55)缺失对饮食诱导肥胖后血糖稳态和胰岛功能的影响。
方法:将GPR55-/-和野生型(WT)小鼠随意饲喂标准食物(SC)或高脂肪饮食(HFD)20周。在饮食干预的9/10和19/20周进行葡萄糖和胰岛素耐量试验。还确定了体内胰岛素分泌和离体胰岛灌注后的动态胰岛素分泌，胰岛caspase-3/7活性和β细胞5-溴-20-脱氧尿苷（BrdU）掺入也是如此。
结果：与维持HFD的WT小鼠相比，饲喂HFD的GPR55-/-小鼠更容易受到饮食诱导的肥胖，并且更不耐受葡萄糖和胰岛素抵抗。从HFD喂养的GPR55-/-小鼠中分离出的胰岛显示葡萄糖和pcachorbol12-肉豆蔻酸酯13-乙酸刺激的胰岛素分泌受损，它们还显示出细胞因子诱导的细胞凋亡增加。尽管饲喂HFD的WT小鼠的胰腺中β细胞BrdU的掺入增加了5.6±1.6倍，在GPR55-/-小鼠中,响应HFD的β细胞增殖的这种代偿性增加减弱.
结论：在饮食诱导的肥胖条件下，GPR55-/-小鼠表现出受损的葡萄糖处理，这与胰岛素分泌能力降低有关，胰岛细胞凋亡增加和β细胞增殖补偿增加不足。这些观察结果支持GPR55在积极调节胰岛功能中起重要作用。
方法:将GPR55-/-和野生型(WT)小鼠随意饲喂标准食物(SC)或高脂肪饮食(HFD)20周。在饮食干预的9/10和19/20周进行葡萄糖和胰岛素耐量试验。还确定了体内胰岛素分泌和离体胰岛灌注后的动态胰岛素分泌，胰岛caspase-3/7活性和β细胞5-溴-20-脱氧尿苷（BrdU）掺入也是如此。
结果：与维持HFD的WT小鼠相比，饲喂HFD的GPR55-/-小鼠更容易受到饮食诱导的肥胖，并且更不耐受葡萄糖和胰岛素抵抗。从HFD喂养的GPR55-/-小鼠中分离出的胰岛显示葡萄糖和pcachorbol12-肉豆蔻酸酯13-乙酸刺激的胰岛素分泌受损，它们还显示出细胞因子诱导的细胞凋亡增加。尽管饲喂HFD的WT小鼠的胰腺中β细胞BrdU的掺入增加了5.6±1.6倍，在GPR55-/-小鼠中,响应HFD的β细胞增殖的这种代偿性增加减弱.
结论：在饮食诱导的肥胖条件下，GPR55-/-小鼠表现出受损的葡萄糖处理，这与胰岛素分泌能力降低有关，胰岛细胞凋亡增加和β细胞增殖补偿增加不足。这些观察结果支持GPR55在积极调节胰岛功能中起重要作用。
