Effects of short-term starvation on the transcriptome and lipid metabolism of epididymal white adipose tissue in mice. Effects of short-term starvation on the transcriptome and lipid metabolism of epididymal white adipose tissue in mice

Beneficial effects have been reported in individuals undergoing fasting to treat excessive weight gain and obesity. To better understand the effects of starvation on the transcriptome and lipid metabolism of white adipose tissue, we established a mouse model of 24-hour fasting using wild type C57BL/6J mice, and performed RNA-seq analysis of the white adipose tissue from the epididymis of fasted mice and control mice. Compared with the control fed mice, these fasted mice showed suppressed lipid synthesis and inhibited insulin signaling, while the lipolysis and gluconeogenesis were enhanced to maintain blood sugar stability. Specifically, the fasted mice had reduced volume of adipose tissues, increased levels of serum NEFA and ANP. In epididymal white adipose tissue, starvation increased the NEFA content, up-regulated the mRNA levels of Atgl, Adrb2, Anp, and Npr1, and promoted the phosphorylation of Hsl. Notably, bioinformatics analysis of the RNA-seq data showed that 24-hour fasting-induced alterations in lipid metabolism was associated with suppressed AMPK signaling and enhanced PPAR signaling in white adipose tissue, which was verified by quantitative PCR. Collectively, these findings supported that starvation promoted the conversion of energy-supplying substrates from glucose to fat. Our work sheds new light on harnessing the plasticity of adipose tissues and the AMPK/PPAR signaling pathways to develop potential strategies to combat obesity and other glucose/lipid metabolisms-associated human diseases. Overall design: After 16-week-old wild-type mice were starved for 24 h, RNA from white adipose tissue in the epididymis of the mice was extracted and transcriptome sequencing was performed. Normal feeding WT mice served as controls. There were 3 biological replicates for each treatment group.

现有研究表明，以禁食手段干预过量体重增加与肥胖的受试者，可观察到有益效应。为深入阐明饥饿状态对白色脂肪组织转录组与脂质代谢的影响，本研究以野生型C57BL/6J小鼠构建24小时禁食模型，并对禁食组与对照组小鼠的附睾白色脂肪组织开展RNA测序（RNA-seq）分析。与正常进食的对照组小鼠相比，禁食小鼠表现出脂质合成受抑、胰岛素信号通路活性下调，同时脂解与糖异生过程增强，以维持血糖稳态。具体而言，禁食小鼠的脂肪组织体积减小，血清游离脂肪酸（NEFA）与心房钠尿肽（ANP）水平升高。在附睾白色脂肪组织中，饥饿状态提升了组织内NEFA含量，上调了脂肪甘油三酯脂肪酶（Atgl）、β2肾上腺素能受体（Adrb2）、心房钠尿肽（Anp）以及钠尿肽受体1（Npr1）的mRNA表达水平，并促进了激素敏感性脂肪酶（Hsl）的磷酸化。值得注意的是，对RNA-seq数据的生物信息学分析显示，24小时禁食诱导的白色脂肪组织脂质代谢改变，与腺苷酸活化蛋白激酶（AMPK）信号通路受抑、过氧化物酶体增殖物激活受体（PPAR）信号通路激活密切相关，该结论经定量聚合酶链反应（quantitative PCR）验证。综上，本研究结果证实，饥饿状态可促使能量供给底物从葡萄糖向脂肪转化。本研究为利用脂肪组织的可塑性以及AMPK/PPAR信号通路，开发对抗肥胖及其他糖脂代谢相关人类疾病的潜在治疗策略提供了新的研究思路。
实验设计概述：将16周龄的野生型小鼠禁食24小时后，提取其附睾白色脂肪组织的总RNA并进行转录组测序。以正常进食的野生型小鼠作为对照组，每组设置3个生物学重复。