Mammalian Genetics Unit and Mary Lyon Centre, MRC Harwell Institute, Didcot, Oxon, UK.
Department of Physiology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Centre, Nijmegen, The Netherlands.
FASEB J. 2023 Nov;37(11):e23211. doi: 10.1096/fj.202201918R.
ARL15, a small GTPase protein, was linked to metabolic traits in association studies. We aimed to test the Arl15 gene as a functional candidate for metabolic traits in the mouse. CRISPR/Cas9 germline knockout (KO) of Arl15 showed that homozygotes were postnatal lethal and exhibited a complete cleft palate (CP). Also, decreased cell migration was observed from Arl15 KO mouse embryonic fibroblasts (MEFs). Metabolic phenotyping of heterozygotes showed that females had reduced fat mass on a chow diet from 14 weeks of age. Mild body composition phenotypes were also observed in heterozygous mice on a high-fat diet (HFD)/low-fat diet (LFD). Females on a HFD showed reduced body weight, gonadal fat depot weight and brown adipose tissue (BAT) weight. In contrast, in the LFD group, females showed increased bone mineral density (BMD), while males showed a trend toward reduced BMD. Clinical biochemistry analysis of plasma on HFD showed transient lower adiponectin at 20 weeks of age in females. Urinary and plasma Mg concentrations were not significantly different. Our phenotyping data showed that Arl15 is essential for craniofacial development. Adult metabolic phenotyping revealed potential roles in brown adipose tissue and bone development.
ARL15 是一种小 GTPase 蛋白，与关联研究中的代谢特征有关。我们旨在测试 Arl15 基因作为代谢特征的功能性候选基因在小鼠中的作用。CRISPR/Cas9 基因敲除（KO）Arl15 显示纯合子在出生后是致命的，并表现出完全的腭裂（CP）。此外，还观察到 Arl15 KO 小鼠胚胎成纤维细胞（MEF）的细胞迁移减少。杂合子的代谢表型显示，雌性在 14 周龄时，在标准饮食中脂肪量减少。在高脂肪饮食（HFD）/低脂肪饮食（LFD）中，杂合子也观察到轻微的身体成分表型。在 HFD 组中，雌性的体重、性腺脂肪储存量和棕色脂肪组织（BAT）重量减少。相比之下，在 LFD 组中，雌性的骨矿物质密度（BMD）增加，而雄性的 BMD 则呈下降趋势。HFD 血浆的临床生化分析显示，雌性在 20 周龄时，瘦素素短暂降低。尿镁和血浆镁浓度无显著差异。我们的表型数据表明，Arl15 对颅面发育至关重要。成年代谢表型显示在棕色脂肪组织和骨骼发育方面有潜在作用。
