Cold-Induced Changes in Gene Expression in Brown Adipose Tissue, White Adipose Tissue and Liver

Cold exposure imposes a metabolic challenge to mammals that is met by a coordinated response in different tissues to prevent hypothermia. This study reports a transcriptomic analysis in brown adipose tissue (BAT), white adipose (WAT) and liver of mice in response to 24 h cold exposure at 8°C. Expression of 1895 genes were significantly (P<0.05) up- or down-regulated more than two fold by cold exposure in all tissues but only 5 of these genes were shared by all three tissues, and only 19, 14 and 134 genes were common between WAT and BAT, WAT and liver, and BAT and liver, respectively. We confirmed using qRT-PCR, the increased expression of a number of characteristic BAT genes during cold exposure. In both BAT and the liver, the most common direction of change in gene expression was suppression (496 genes in BAT and 590 genes in liver). Gene ontology analysis revealed for the first time significant (P<0.05) down regulation in response to cold, of genes involved in oxidoreductase activity, lipid metabolic processes and protease inhibitor activity, in both BAT and liver, but not WAT. The results reveal an unexpected importance of down regulation of cytochrome P450 gene expression and apolipoprotein, in both BAT and liver, but not WAT, in response to cold exposure. Pathway analysis suggests a model in which down regulation of the nuclear transcription factors HNF4α and PPARα in both BAT and liver may orchestrate the down regulation of genes involved in lipoprotein and steroid metabolism as well as Phase I enzymes belonging to the cytochrome P450 group in response to cold stress in mice. We propose that the response to cold stress involves decreased gene expression in a range of cellular processes in order to maximise pathways involved in heat production.

寒冷暴露对哺乳动物构成代谢挑战，机体需通过不同组织的协同应答以预防低体温症（hypothermia）。本研究针对小鼠在8℃环境下接受24小时寒冷暴露后的棕色脂肪组织（brown adipose tissue, BAT）、白色脂肪组织（white adipose, WAT）及肝脏开展转录组分析（transcriptomic analysis）。结果显示，在所有三种组织中，共有1895个基因的表达量因寒冷暴露发生显著（P<0.05）上调或下调，且变化幅度超过2倍；但其中仅5个基因在三种组织中均存在表达差异，而白色脂肪组织与棕色脂肪组织、白色脂肪组织与肝脏、棕色脂肪组织与肝脏之间共有的差异基因分别仅为19个、14个和134个。我们通过实时定量逆转录聚合酶链反应（qRT-PCR）验证了寒冷暴露下多种特征性棕色脂肪组织基因的表达上调现象。在棕色脂肪组织与肝脏中，基因表达变化最常见的方向为表达抑制，其中棕色脂肪组织中共496个基因、肝脏中共590个基因出现表达抑制。基因本体论（Gene Ontology, GO）分析首次发现，寒冷暴露下棕色脂肪组织与肝脏中参与氧化还原酶活性、脂质代谢过程及蛋白酶抑制剂活性的基因均出现显著（P<0.05）下调，而白色脂肪组织中未观察到此现象。研究结果还揭示了一项未被预期的重要发现：寒冷暴露下棕色脂肪组织与肝脏中细胞色素P450（cytochrome P450）家族基因及载脂蛋白（apolipoprotein）的表达出现下调，而白色脂肪组织中并无此变化。通路分析提示，小鼠在寒冷应激下，棕色脂肪组织与肝脏中核转录因子HNF4α与PPARα的下调可能协同调控脂蛋白、类固醇代谢相关基因及细胞色素P450家族I相酶的表达下调。我们提出，寒冷应激应答涉及一系列细胞过程的基因表达降低，以最大化产热相关通路的活性。