METHODS: This study investigated the consequences of cold exposure on the BAT and liver proteomes of an established CMD mouse model based on LDL receptor-deficient (LdlrKO) mice fed a high-fat, high-sucrose, high-cholesterol diet for 16 weeks. We analyzed energy metabolism in vivo and performed untargeted proteomics on BAT and liver of LdlrKO mice maintained at 22 °C or 5 °C for 7 days.
RESULTS: We identified several dysregulated pathways, miRNAs, and transcription factors in BAT and liver of cold-exposed Ldlrko mice that have not been previously described in this context. Networks of regulatory interactions based on shared downstream targets and analysis of ligand-receptor pairs identified fibrinogen alpha chain (FGA) and fibronectin 1 (FN1) as potential crosstalk factors between BAT and liver in response to cold exposure. Importantly, genetic variations in the genes encoding FGA and FN1 have been associated with cardiometabolic-related phenotypes and traits in humans.
CONCLUSIONS: This study describes the key factors, pathways, and regulatory networks involved in the crosstalk between BAT and the liver in a cold-exposed CMD mouse model. These findings may provide a basis for future studies aimed at testing whether molecular mediators, as well as regulatory and signaling mechanisms involved in tissue adaption upon cold exposure, could represent a target in cardiometabolic disorders.
方法:这项研究调查了寒冷暴露对建立的CMD小鼠模型的BAT和肝脏蛋白质组的影响,该模型基于高脂肪,高蔗糖,高胆固醇饮食16周。我们分析了体内能量代谢,并对22°C或5°C维持7天的LdlrKO小鼠的BAT和肝脏进行了非靶向蛋白质组学。
结果:我们确定了几种失调的途径,miRNA,以及冷暴露Ldlrko小鼠的BAT和肝脏中的转录因子,这些转录因子以前没有在本文中描述过。基于共享下游靶标的调节相互作用网络和配体-受体对的分析将纤维蛋白原α链(FGA)和纤连蛋白1(FN1)确定为响应冷暴露的BAT和肝脏之间的潜在串扰因素。重要的是,编码FGA和FN1基因的遗传变异与人类心脏代谢相关表型和性状相关.
结论:这项研究描述了关键因素,通路,在冷暴露的CMD小鼠模型中,BAT和肝脏之间的串扰涉及调节网络。这些发现可能为未来的研究提供基础,旨在测试分子介质是否,以及冷暴露时组织适应的调节和信号机制,可能代表心脏代谢紊乱的目标。