Poitout V, Rouault C, Guerre-Millo M, Briaud I, Reach G
INSERM U341, Service de Diabétologie, Paris, France.
Endocrinology. 1998 Mar;139(3):822-6. doi: 10.1210/endo.139.3.5812.
The recently discovered adipose cell-specific hormone called leptin decreases food intake and increases energy expenditure in rodents through a pathway involving hypothalamic leptin receptors, OB-R. In addition, leptin decreases insulin circulating levels independent of the reduction in food intake. Whether or not the hormone has a direct effect on pancreatic beta-cells is not clear, because previous in vitro studies have led to controversial results depending on the animal model used. The present study was designed to investigate the effects of leptin in islets of Langerhans isolated from normal rodents. Three isoforms of the leptin receptor, OB-Ra, b, and f, were detected by RT-PCR analysis of total RNA from rat islets. In static incubations, leptin (10 ng/ml) did not alter basal insulin secretion nor insulin secretion stimulated by glucose alone, potassium chloride, or ketoisocaproic acid. In contrast, insulin secretion stimulated by glucose + 3-isobutyl 1-methylxanthine (IBMX) was inhibited by 34 +/- 15% (n = 4, P < 0.05). This was further substantiated in perifusion experiments, in which leptin decreased by 31 +/- 3% (n = 5, P < 0.01) glucose + IBMX-stimulated insulin release. Similarly, in mouse islets a significant inhibitory effect of leptin (-31 +/- 4%, n = 6, P < 0.05) was observed only on glucose + IBMX-stimulated insulin secretion, with no effect of the hormone on basal nor glucose-stimulated secretion. Finally, leptin was totally inefficient in islets isolated from obese fa/fa rats, which bear a mutation in OB-R. These results suggest that, in normal rodent islets, leptin specifically inhibits IBMX-potentiated glucose-induced insulin secretion, through a direct effect involving at least one of the three isoforms of OB-R expressed in islets.
最近发现的一种名为瘦素的脂肪细胞特异性激素，通过一条涉及下丘脑瘦素受体OB-R的途径，减少啮齿动物的食物摄入量并增加能量消耗。此外，瘦素可降低循环胰岛素水平，且与食物摄入量的减少无关。该激素是否对胰腺β细胞有直接作用尚不清楚，因为先前的体外研究根据所使用的动物模型得出了有争议的结果。本研究旨在探讨瘦素对从正常啮齿动物分离出的胰岛的影响。通过对大鼠胰岛总RNA进行RT-PCR分析，检测到了瘦素受体的三种亚型，即OB-Ra、b和f。在静态孵育中，瘦素（10 ng/ml）既不改变基础胰岛素分泌，也不改变单独由葡萄糖、氯化钾或酮异己酸刺激引起的胰岛素分泌。相比之下，葡萄糖+3-异丁基-1-甲基黄嘌呤（IBMX）刺激的胰岛素分泌受到抑制，抑制率为34±15%（n = 4，P < 0.05）。这在灌注实验中得到了进一步证实，在灌注实验中，瘦素使葡萄糖+IBMX刺激的胰岛素释放减少了31±3%（n = 5，P < 0.01）。同样，在小鼠胰岛中，仅观察到瘦素对葡萄糖+IBMX刺激的胰岛素分泌有显著抑制作用（-31±4%，n = 6，P < 0.05），而该激素对基础分泌或葡萄糖刺激的分泌均无影响。最后，瘦素对从肥胖fa/fa大鼠分离出的胰岛完全无效，这些大鼠的OB-R存在突变。这些结果表明，在正常啮齿动物胰岛中，瘦素通过涉及胰岛中表达的三种OB-R亚型中至少一种的直接作用，特异性抑制IBMX增强的葡萄糖诱导的胰岛素分泌。
