Sexually dimorphic roles for the type 2 diabetes-associated C2cd4b gene in murine glucose homeostasis.
Sexually dimorphic roles for the type 2 diabetes-associated C2cd4b gene in murine glucose homeostasis.
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DOI：
10.1007/s00125-020-05350-x
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发表时间：
2021-04
期刊：
影响因子：
8.2
通讯作者：
Rutter GA
中科院分区：
文献类型：
--
作者：
Mousavy Gharavy SN;Owen BM;Millership SJ;Chabosseau P;Pizza G;Martinez-Sanchez A;Tasoez E;Georgiadou E;Hu M;Fine NHF;Jacobson DA;Dickerson MT;Idevall-Hagren O;Montoya A;Kramer H;Mehta Z;Withers DJ;Ninov N;Gadue PJ;Cardenas-Diaz FL;Cruciani-Guglielmacci C;Magnan C;Ibberson M;Leclerc I;Voz M;Rutter GA
VPS 13 C/C2CD 4A/C2CD 4 B基因座附近的变异与全基因组关联研究中2型糖尿病风险改变相关虽然先前的功能性工作已经表明VPS 13 C和C2CD 4A在疾病发展中的作用，但没有人探索C2CD 4 B的作用。使用CRISPR/Cas9诱导的C2cd 4 b基因敲除小鼠和c2cd 4a缺失的斑马鱼幼虫来研究该基因在葡萄糖稳态中的作用。产生了用FLAG或绿色荧光蛋白标记的C2钙依赖性结构域包含蛋白（C2 CD）4A和C2 CD 4 B构建体，以使用共聚焦或近场显微镜研究亚细胞动力学，并通过质谱鉴定相互作用的伴侣。C2cd 4 b在小鼠中的系统失活导致体重和葡萄糖稳态的显著但高度性二态性变化。雌性C2cd 4 b小鼠与对照同窝小鼠相比显示体重不变，但葡萄糖耐量异常（AUC，p = 0.01）和体内胰岛素分泌缺陷，但体外胰岛素分泌无缺陷（p = 0.02）。与野生型（WT）同窝仔相比，这与促卵泡激素水平显著降低相关（p = 0.003）。与此形成鲜明对比的是，雄性C2cd 4 b缺失小鼠显示出基本上正常的葡萄糖耐量，但在维持高脂肪和高蔗糖饮食后，体重（p < 0.001）和空腹血糖（p = 0.003）相对于WT同窝出生的小鼠增加。在小鼠中C2cd 4a整体失活后，或在C2cd 4a缺失的斑马鱼的幼虫阶段的胰腺β细胞功能中，未观察到代谢紊乱。在成年C2cd 4a基因缺失的鱼中，空腹血糖水平也没有改变。C2CD 4 B和C2CD 4A部分定位于质膜，后者受细胞内Ca ~（2+）控制。两者的结合伴侣包括分泌颗粒定位的PTPRN 2/phogrin。我们的研究表明，C2cd 4 b可能集中在脑垂体影响性别依赖的电路，控制胰腺β细胞功能和糖耐量的啮齿动物。然而，在糖尿病风险变体的影响中缺乏性二态性，这证明了C2CD 4A或VPS 13 C在人类葡萄糖稳态控制中的额外作用。当前研究期间生成和/或分析的数据集可在Biorxiv存储库（www.biorxiv.org/content/10.1101/2020.05.18.099200v1）中获得。RNA-Seq（GSE 152576）和蛋白质组学（PXD 021597）数据已存入GEO（www.ncbi.nlm.nih.gov/geo/query/acc.cgi? acc= GSE 152576）和ProteomeXchange（www.ebi.ac.uk/pride/archive/projects/PXD 021597）存储库。在线版本包含同行评审但未经编辑的补充材料，可通过10.1007/s 00125 -020-05350-x获得。
Variants close to the VPS13C/C2CD4A/C2CD4B locus are associated with altered risk of type 2 diabetes in genome-wide association studies. While previous functional work has suggested roles for VPS13C and C2CD4A in disease development, none has explored the role of C2CD4B. CRISPR/Cas9-induced global C2cd4b-knockout mice and zebrafish larvae with c2cd4a deletion were used to study the role of this gene in glucose homeostasis. C2 calcium dependent domain containing protein (C2CD)4A and C2CD4B constructs tagged with FLAG or green fluorescent protein were generated to investigate subcellular dynamics using confocal or near-field microscopy and to identify interacting partners by mass spectrometry. Systemic inactivation of C2cd4b in mice led to marked, but highly sexually dimorphic changes in body weight and glucose homeostasis. Female C2cd4b mice displayed unchanged body weight compared with control littermates, but abnormal glucose tolerance (AUC, p = 0.01) and defective in vivo, but not in vitro, insulin secretion (p = 0.02). This was associated with a marked decrease in follicle-stimulating hormone levels as compared with wild-type (WT) littermates (p = 0.003). In sharp contrast, male C2cd4b null mice displayed essentially normal glucose tolerance but an increase in body weight (p < 0.001) and fasting blood glucose (p = 0.003) after maintenance on a high-fat and -sucrose diet vs WT littermates. No metabolic disturbances were observed after global inactivation of C2cd4a in mice, or in pancreatic beta cell function at larval stages in C2cd4a null zebrafish. Fasting blood glucose levels were also unaltered in adult C2cd4a-null fish. C2CD4B and C2CD4A were partially localised to the plasma membrane, with the latter under the control of intracellular Ca2+. Binding partners for both included secretory-granule-localised PTPRN2/phogrin. Our studies suggest that C2cd4b may act centrally in the pituitary to influence sex-dependent circuits that control pancreatic beta cell function and glucose tolerance in rodents. However, the absence of sexual dimorphism in the impact of diabetes risk variants argues for additional roles for C2CD4A or VPS13C in the control of glucose homeostasis in humans. The datasets generated and/or analysed during the current study are available in the Biorxiv repository (www.biorxiv.org/content/10.1101/2020.05.18.099200v1). RNA-Seq (GSE152576) and proteomics (PXD021597) data have been deposited to GEO (www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE152576) and ProteomeXchange (www.ebi.ac.uk/pride/archive/projects/PXD021597) repositories, respectively. The online version contains peer-reviewed but unedited supplementary material available at 10.1007/s00125-020-05350-x.
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雌激素受体ERα调节胰腺胰岛素含量。
影响因子：
3.7
作者：
Alonso-Magdalena, Paloma;Ropero, Ana B.;Carrera, M. Pilar;Cederroth, Christopher R.;Baquie, Mathurin;Gauthier, Benoit R.;Nef, Serge;Stefani, Enrico;Nadal, Angel
通讯作者：
Nadal, Angel
影响因子：
3.7
作者：
Marselli L;Thorne J;Dahiya S;Sgroi DC;Sharma A;Bonner-Weir S;Marchetti P;Weir GC
通讯作者：
Weir GC
影响因子：
2.7
作者：
Mavropoulos, A;Devos, N;Peers, B
通讯作者：
Peers, B
影响因子：
11.4
作者：
Idevall-Hagren, Olof;Lue, Alice;De Camilli, Pietro
通讯作者：
De Camilli, Pietro
DOI：
10.1007/978-3-319-70178-3_1
发表时间：
2017-01-01
期刊：
SEX AND GENDER FACTORS AFFECTING METABOLIC HOMEOSTASIS, DIABETES AND OBESITY
影响因子：
--
作者：
Mauvais-Jarvis, Franck
通讯作者：
Mauvais-Jarvis, Franck