β Cell-specific deletion of guanylyl cyclase A, the receptor for atrial natriuretic peptide, accelerates obesity-induced glucose intolerance in mice.
β Cell-specific deletion of guanylyl cyclase A, the receptor for atrial natriuretic peptide, accelerates obesity-induced glucose intolerance in mice.
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DOI：
10.1186/s12933-018-0747-3
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发表时间：
2018-07-17
影响因子：
9.3
通讯作者：
Kuhn M
中科院分区：
文献类型：
--
作者：
Tauscher S;Nakagawa H;Völker K;Werner F;Krebes L;Potapenko T;Doose S;Birkenfeld AL;Baba HA;Kuhn M
心脏激素心钠素(ANP)和B型利钠肽(BNP)通过其共同的cGMP产生鸟苷酸环化酶-A(GC-A)受体调节动脉血压，改善能量代谢和胰岛素敏感性。肥胖与NP/GC-A/cGMP信号通路受损有关，可能与2型糖尿病及其心脏代谢并发症的发生有关。在体外，人工合成的心钠素通过GC-A刺激培养的胰岛释放葡萄糖依赖的胰岛素和β细胞的增殖。然而，体内系统性葡萄糖稳态的相关性尚不清楚。为了分析体内病理生理条件下内源性心脏激素是否调节β细胞的分泌功能和/或增殖，我们建立了一种新的选择性阻断β细胞GC-A受体的遗传性小鼠模型。将携带GC-A基因的小鼠培育成RIP-CRTG小鼠，从而选择性地删除β细胞中的GC-A(βGC-A KO)。监测了正常饮食(ND)和高脂饮食(HFD)喂养的小鼠的体重增加、葡萄糖耐量、胰岛素敏感性和葡萄糖刺激的胰岛素分泌。用免疫荧光法测定β细胞的大小和数量。在体外，心钠素对βGC-A KO小鼠分离的胰岛细胞的促胰岛素和促增殖作用被取消。与之一致的是，在体内，注射BNP可轻微提高对照组小鼠的基础血浆胰岛素水平和葡萄糖诱导的胰岛素分泌。在βGC-A KO小鼠中，外源性脑钠素的这种作用被取消，证实了β-细胞中GC-A受体的有效失活。尽管如此，在生理ND条件下，βGC-A KO小鼠和对照仔鼠的胰岛素水平、空腹和喂养胰岛素水平、葡萄糖诱导的胰岛素分泌、葡萄糖耐量和β细胞形态都是相似的。然而，高脂饲料喂养的βGC-A KO动物糖耐量增加，适应性β细胞增殖减弱。我们对βGC-A KO小鼠的研究表明，心脏激素心钠素和脑钠素在生理和正常饮食条件下不调节β细胞的生长和分泌功能。然而，内源性NP/GC-A信号通路改善了β细胞对高脂饮食诱导的肥胖的初始适应性反应。肥胖者β细胞NP/GC-A信号受损可能与2型糖尿病的发生有关。
The cardiac hormones atrial (ANP) and B-type natriuretic peptides (BNP) moderate arterial blood pressure and improve energy metabolism as well as insulin sensitivity via their shared cGMP-producing guanylyl cyclase-A (GC-A) receptor. Obesity is associated with impaired NP/GC-A/cGMP signaling, which possibly contributes to the development of type 2 diabetes and its cardiometabolic complications. In vitro, synthetic ANP, via GC-A, stimulates glucose-dependent insulin release from cultured pancreatic islets and β-cell proliferation. However, the relevance for systemic glucose homeostasis in vivo is not known. To dissect whether the endogenous cardiac hormones modulate the secretory function and/or proliferation of β-cells under (patho)physiological conditions in vivo, here we generated a novel genetic mouse model with selective disruption of the GC-A receptor in β-cells. Mice with a floxed GC-A gene were bred to Rip-CreTG mice, thereby deleting GC-A selectively in β-cells (β GC-A KO). Weight gain, glucose tolerance, insulin sensitivity, and glucose-stimulated insulin secretion were monitored in normal diet (ND)- and high-fat diet (HFD)-fed mice. β-cell size and number were measured by immunofluorescence-based islet morphometry. In vitro, the insulinotropic and proliferative actions of ANP were abolished in islets isolated from β GC-A KO mice. Concordantly, in vivo, infusion of BNP mildly enhanced baseline plasma insulin levels and glucose-induced insulin secretion in control mice. This effect of exogenous BNP was abolished in β GC-A KO mice, corroborating the efficient inactivation of the GC-A receptor in β-cells. Despite this under physiological, ND conditions, fasted and fed insulin levels, glucose-induced insulin secretion, glucose tolerance and β-cell morphology were similar in β GC-A KO mice and control littermates. However, HFD-fed β GC-A KO animals had accelerated glucose intolerance and diminished adaptative β-cell proliferation. Our studies of β GC-A KO mice demonstrate that the cardiac hormones ANP and BNP do not modulate β-cell’s growth and secretory functions under physiological, normal dietary conditions. However, endogenous NP/GC-A signaling improves the initial adaptative response of β-cells to HFD-induced obesity. Impaired β-cell NP/GC-A signaling in obese individuals might contribute to the development of type 2 diabetes.
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影响因子：
4.8
作者：
Moro, C;Crampes, F;Berlan, M
通讯作者：
Berlan, M
影响因子：
7.7
作者：
Mezza T;Muscogiuri G;Sorice GP;Clemente G;Hu J;Pontecorvi A;Holst JJ;Giaccari A;Kulkarni RN
通讯作者：
Kulkarni RN
影响因子：
9.3
作者：
Nunes, Sara;Soares, Edna;Reis, Flavio
通讯作者：
Reis, Flavio
DOI：
10.1152/ajpendo.90227.2008
发表时间：
2008-08-01
影响因子：
5.1
作者：
Moro, Cedric;Pillard, Fabien;Berlan, Michel
通讯作者：
Berlan, Michel
影响因子：
3.7
作者：
Jujić A;Nilsson PM;Engström G;Hedblad B;Melander O;Magnusson M
通讯作者：
Magnusson M