Limited impact on glucose homeostasis of leptin receptor deletion from insulin- or proglucagon-expressing cells.
Limited impact on glucose homeostasis of leptin receptor deletion from insulin- or proglucagon-expressing cells.
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DOI：
10.1016/j.molmet.2015.06.007
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发表时间：
2015-09
影响因子：
8.1
通讯作者：
Rutter GA
中科院分区：
文献类型：
--
作者：
Soedling H;Hodson DJ;Adrianssens AE;Gribble FM;Reimann F;Trapp S;Rutter GA
脂肪组织衍生激素瘦素在维持体重和血糖动态平衡方面起着重要作用。瘦素通过与瘦素受体(LepRb)的相互作用来调节其作用，LepRb在下丘脑和其他大脑中心高度表达，在外周表达水平较低。以前的研究分别使用相对杂乱或低效的Cre缺失菌株来探索LepR在胰腺β和α细胞中的作用。在这里，我们使用两个新开发的Cre系来探索瘦素信号在胰岛素和胰高血糖素原表达细胞中的作用。用RNAseq和定量RT-PCR检测分离的小鼠胰岛和高纯度胰岛细胞中瘦素受体的表达。分别用Ins1Cre或iGluCre介导的Flx‘d瘦素受体等位基因重组产生在胰腺β、α和其他前高血糖素表达细胞中缺乏瘦素信号的小鼠。在体内葡萄糖稳态中，使用标准技术评估体重、胰腺组织学和孤立胰岛激素分泌的变化。在野生型成年小鼠分离的胰岛和纯化的细胞中，瘦素受体的mRNA水平处于或低于检测水平，并且没有检测到瘦素对STAT3磷酸化的信号。虽然在β细胞中进一步缺失瘦素受体的雄性小鼠在16周龄之前没有表现出糖耐量异常，但雌性小鼠在8周时表现出短暂的糖耐量改善(曲线下面积减少11.2%±33.2%；P<0.05)，并在体外改善了葡萄糖刺激的胰岛素分泌(39.0%±13.0%，P<0.05)。在体重、空腹血糖和β/α细胞比率方面，不同基因型之间没有差异。从α细胞、少数β细胞和大脑中表达胰高血糖素原的细胞亚群中删除LEPR，对体重、葡萄糖或胰岛素耐受性没有影响，也没有对体内和体外评估的胰腺激素分泌产生影响。这里使用的高选择性Cre重组酶表明，瘦素信号在小鼠β细胞功能的控制中起着相对次要的、年龄和性别相关的作用。在本研究中，没有发现α细胞上的瘦素受体在体内的作用，也没有在其他表达前高血糖素的细胞中检测到瘦素受体的作用。β细胞瘦素受体在血糖稳态中的作用不大。α细胞瘦素受体不参与低血糖反应。体重维持不需要瘦素对GLP-1分泌细胞的作用。
The adipose tissue-derived hormone leptin plays an important role in the maintenance of body weight and glucose homeostasis. Leptin mediates its effects by interaction with leptin receptors (LepRb), which are highly expressed in the hypothalamus and other brain centres, and at lower levels in the periphery. Previous studies have used relatively promiscuous or inefficient Cre deleter strains, respectively, to explore the roles of LepR in pancreatic β and α cells. Here, we use two newly-developed Cre lines to explore the role of leptin signalling in insulin and proglucagon-expressing cells. Leptin receptor expression was measured in isolated mouse islets and highly-purified islet cells by RNASeq and quantitative RT-PCR. Mice lacking leptin signalling in pancreatic β, or in α and other proglucagon-expressing cells, were generated using Ins1Cre- or iGluCre-mediated recombination respectively of flox'd leptin receptor alleles. In vivo glucose homeostasis, changes in body weight, pancreatic histology and hormone secretion from isolated islets were assessed using standard techniques. Leptin receptor mRNA levels were at or below the level of detection in wild-type adult mouse isolated islets and purified cells, and leptin signalling to Stat3 phosphorylation was undetectable. Whereas male mice further deleted for leptin receptors in β cells exhibited no abnormalities in glucose tolerance up to 16 weeks of age, females transiently displayed improved glucose tolerance at 8 weeks (11.2 ± 3.2% decrease in area under curve; p < 0.05), and improved (39.0 ± 13.0%, P < 0.05) glucose-stimulated insulin secretion in vitro. No differences were seen between genotypes in body weight, fasting glucose or β/α cell ratio. Deletion of LepR from α-cells, a minority of β cells, and a subset of proglucagon-expressing cells in the brain, exerted no effects on body weight, glucose or insulin tolerance, nor on pancreatic hormone secretion assessed in vivo and in vitro. The use here of a highly selective Cre recombinase indicates that leptin signalling plays a relatively minor, age- and sex-dependent role in the control of β cell function in the mouse. No in vivo role for leptin receptors on α cells, nor in other proglucagon-expressing cells, was detected in this study. β cell leptin receptors play a minor role in glucose homeostasis. α cell leptin receptors are not involved in responses to hypoglycaemia. Body weight maintenance does not require leptin action on GLP-1-secreting cells.