Warming Induces Significant Reprogramming of Beige, but Not Brown, Adipocyte Cellular Identity. Warming Induces Significant Reprogramming of Beige, but Not Brown, Adipocyte Cellular Identity

Beige and brown adipocytes generate heat in response to reductions in ambient temperature. When warmed, both beige and brown adipocytes exhibit morphological ‘whitening’, but it is unknown whether or to what extent this represents a true shift in cellular identity. Using cell type-specific profiling in vivo, we uncover a unique paradigm of temperature-dependent epigenomic plasticity of beige, but not brown, adipocytes, with conversion from a brown to a white chromatin state. Despite this profound shift in cellular identity, warm whitened beige adipocytes retain an epigenomic memory of prior cold exposure defined by an array of poised enhancers that prime thermogenic genes for rapid response during a second bout of cold exposure. We further show that a transcriptional cascade involving the glucocorticoid receptor and Zfp423 can drive warm-induced whitening of beige adipocytes. These studies identify the epigenomic and transcriptional bases of an extraordinary example of cellular plasticity in response to environmental signals. Overall design: Ucp1-NuTRAP and Adipoq-NuTRAP mice exposed to different temperatures were used for brown, beige or white adipocyte-specific transcriptomic and epigenomic analysis.

米色脂肪细胞（beige adipocytes）与棕色脂肪细胞（brown adipocytes）可响应环境温度降低而产热。当处于加温环境时，两类脂肪细胞均会呈现形态学上的“白色化”特征，但目前尚不清楚该变化是否代表细胞身份的真正转变，以及转变的具体程度。本研究借助体内细胞类型特异性谱分析（cell type-specific profiling），揭示了米色而非棕色脂肪细胞存在一种独特的温度依赖性表观基因组可塑性范式：其染色质状态会从棕色样向白色样发生转换。尽管细胞身份发生了显著转变，经加温诱导白色化的米色脂肪细胞仍保留了先前寒冷暴露的表观基因组记忆，该记忆由一系列 poised增强子（poised enhancers）所定义，这些增强子可预先致敏产热基因，使其在再次遭遇寒冷暴露时能够快速响应。本研究进一步证实，一条涉及糖皮质激素受体（glucocorticoid receptor）与Zfp423的转录级联反应，可驱动加温诱导的米色脂肪细胞白色化过程。本研究明确了这一响应环境信号的极端细胞可塑性案例的表观基因组与转录调控基础。整体实验设计：将暴露于不同温度环境的Ucp1-NuTRAP与Adipoq-NuTRAP小鼠，用于棕色、米色或白色脂肪细胞的特异性转录组与表观基因组分析。