Early life stress exacerbates obesity in adult female mice via mineralocorticoid receptor-dependent increases in adipocyte triglyceride and glycerol content.
Early life stress exacerbates obesity in adult female mice via mineralocorticoid receptor-dependent increases in adipocyte triglyceride and glycerol content.
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早期生活压力通过盐皮质激素受体依赖性脂肪细胞甘油三酯和甘油含量的增加加剧了成年雌性小鼠的肥胖。
DOI：
10.1016/j.lfs.2022.120718
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发表时间：
2022
期刊：
影响因子：
6.1
通讯作者：
Loria,AnaliaS
中科院分区：
文献类型：
--
作者：
Leachman,JacquelineR;Cincinelli,Cole;Ahmed,Nermin;Dalmasso,Carolina;Xu,Mei;Gatineau,Eva;Nikolajczyk,BarbaraS;Yiannikouris,Frederique;HindsJr,TerryD;Loria,AnaliaS
以前，我们已经表明，母亲分离和早期断奶（MSEW）加剧高脂肪饮食（HF）诱导的内脏肥胖的雌性后代相比，正常饲养的雌性小鼠。应激激素如糖皮质激素和盐皮质激素是脂肪扩张过程中的关键介质，并且两者都可以激活脂肪细胞中的盐皮质激素受体（MR）。因此，本研究旨在了解MSEW对脂肪组织基本稳态功能的具体影响，并研究雌性MSEW小鼠是否表现出由MR介导的加重的致肥胖反应。收集一种内脏脂肪的性腺白色脂肪组织（gWAT）以评估脂质组学、转录组学和体外脂解测定。与肥胖对照小鼠相比，肥胖雌性MSEW小鼠表现出肥胖增加、44：2/FA 18：2 + NH 4脂质类升高和线粒体DNA密度降低。此外，在分离的前和成熟脂肪细胞中的单细胞RNA测序显示水甘油孔蛋白3（Aqp 3）下调约9倍，水甘油孔蛋白3是脂肪细胞中负责甘油流出的通道。与对照组相比，肥胖的MSEW小鼠显示出高水平的循环醛固酮和gWAT衍生的皮质酮。此外，与对照组相比，MR阻断剂螺内酯（Spiro，100 mg/kg/天，2周）使MSEW小鼠中升高的细胞内甘油水平、更大的体外脂解反应和大尺寸脂肪细胞的数量正常化。我们的数据表明，MR通过甘油释放阻止脂解，促进甘油三酯形成和储存，从而促进雌性MSEW小鼠脂肪细胞肥大。
Previously, we have shown that Maternal Separation and Early Weaning (MSEW) exacerbates high fat diet (HF)-induced visceral obesity in female offspring compared to normally reared female mice. Stress hormones such as glucocorticoids and mineralocorticoids are critical mediators in the process of fat expansion, and both can activate the mineralocorticoid receptor (MR) in the adipocyte. Therefore, this study aimed to, comprehend the specific effects of MSEW on adipose tissue basic homeostatic function, and investigate whether female MSEW mice show an exacerbated obesogenic response mediated by MR. Gonadal white adipose tissue (gWAT), a type of visceral fat, was collected to assess lipidomics, transcriptomics, and in vitro lipolysis assay. Obese female MSEW mice showed increased adiposity, elevated 44:2/FA 18:2 + NH4 lipid class and reduced mitochondrial DNA density compared to obese control counterparts. In addition, single-cell RNA sequencing in isolated pre- and mature adipocytes showed a ~9-fold downregulation of aquaglycerolporin 3 (Aqp3), a channel responsible for glycerol efflux in adipocytes. Obese MSEW mice showed high levels of circulating aldosterone and gWAT-derived corticosterone compared to controls. Further, the MR blocker spironolactone (Spiro, 100 mg/kg/day, 2 weeks) normalized the elevated intracellular glycerol levels, the greater in vitro lipolysis response, and the number of large size adipocytes in MSEW mice compared to the controls. Our data suggests that MR plays a role promoting adipocyte hypertrophy in female MSEW mice by preventing lipolysis via glycerol release in favor of triglyceride formation and storage.