Macrophages and brown adipocytes cross-communicate to modulate a thermogenic program following methamphetamine exposure.

Hyperthermia is a potentially lethal side-effect of Methamphetamine (Meth), a stimulant drug. Activation of non-shivering thermogenesis in brown adipose tissue (BAT) is partly responsible for Meth-induced rise in temperature, with contributing sympathetic neurotransmitters, such as norepinephrine (NE), and reactive oxygen species (ROS). However, the mechanisms controlling the development of a molecular thermogenic program in brown adipocytes (BA) following Meth are unknown. We hypothesize that Meth and NE affect BAT cells, BA and macrophages, to modify their physiology and interactions, with consequences to thermogenic genes. We also hypothesize that ROS play a critical role in signaling transcription of thermogenic genes and their regulatory components. Using primary BA and macrophage cultures, we measured Meth and NE interference with physiological and phenotypic measures that are relevant to thermogenesis in BAT. Meth caused both BA and macrophages to decrease mitochondrial maximal capacity and increase ROS. In BA, the thermogenic genes UCP1, PPARγ, PGC1α and GADD45γ were transcriptionally increased by Meth in a ROS-dependent manner. In macrophages, Meth increased oxidative stress response and caused a predominance of M2 subset markers. BA transcriptional changes in response to Meth and NE were significantly controlled by macrophages. The results suggest that BA and macrophages respond to Meth and NE, with effects on mitochondrial functions and transcription of genes involved in thermogenesis. ROS-dependent signals in BA and cellular interactions between BA and macrophages synergize to regulate the BAT environment and control critical pathways leading to Meth-hyperthermia.

高热是甲基苯丙胺（冰毒）这种兴奋剂的一种潜在致命副作用。棕色脂肪组织（BAT）中非战栗产热的激活是冰毒诱导体温升高的部分原因，其中交感神经递质如去甲肾上腺素（NE）和活性氧物质（ROS）也起了作用。然而，冰毒作用后控制棕色脂肪细胞（BA）中分子产热程序发展的机制尚不清楚。我们假设冰毒和NE影响BAT细胞、BA和巨噬细胞，改变它们的生理机能和相互作用，进而影响产热基因。我们还假设ROS在产热基因及其调控成分的转录信号传导中起关键作用。利用原代BA和巨噬细胞培养物，我们测量了冰毒和NE对与BAT产热相关的生理和表型指标的干扰。冰毒导致BA和巨噬细胞的线粒体最大产能降低，ROS增加。在BA中，产热基因UCP1、PPARγ、PGC1α和GADD45γ被冰毒以ROS依赖的方式转录上调。在巨噬细胞中，冰毒增加氧化应激反应，并导致M2亚群标志物占优势。BA对冰毒和NE反应的转录变化受到巨噬细胞的显著调控。结果表明，BA和巨噬细胞对冰毒和NE有反应，影响线粒体功能和参与产热的基因转录。BA中的ROS依赖信号以及BA和巨噬细胞之间的细胞相互作用协同调节BAT环境并控制导致冰毒高热的关键途径。