Cold-Responsive DPP4+ Progenitor Cells Facilitate Thermogenic Remodeling of Subcutaneous Adipose Tissue_isoproterenol treatment

The physiological adaptation to cold environmental temperatures involves the remodeling of energy-storing white adipose tissue (WAT) into an energy-burning thermogenic phenotype, characterized by the emergence of multi-locular beige adipocytes. To date, the full array of cold-responsive cells within WAT that mediate thermogenic remodeling remain undefined. Here, we demonstrate that distinct perivascular PDGFRb+ adipocyte precursor cell (APC) subpopulations are differentially sensitive to cold temperatures in vivo. One day of cold exposure elicits striking transcriptional changes in DPP4+ PDGFRb+ APCs, whereas committed DPP4- PDGFRb+ preadipocytes appear comparatively much less responsive. This adaptation includes beta-adrenergic receptor mediated induction in the expression of the pro-thermogenic cytokine, IL-33. DPP4+ PDGFRb+ cells represent the sole source of IL-33 within inguinal WAT of adult mice. Doxycycline-inducible deletion of Il33 in PDGFRb+ cells at the onset of cold exposure significantly compromises the thermogenic remodeling of WAT without directly impacting the differentiation capacity of APCs per se. Together, these studies reveal the presence of a cold-responsive progenitor cell subpopulation in adult WAT and highlight their ability to regulate tissue plasticity through the production of immunological factors. Overall design: Bulk RNA-seq experiment to analyze gene expression profile of cultured inguinal primary white adipose tissue DPP4_neg APCs and DPP4_pos APCs treated with vehicle (PBS) or 10mM isoproterenol for 4 hours.

机体对寒冷环境温度的生理适应，表现为储能型白色脂肪组织（white adipose tissue, WAT）被重塑为产热表型，其核心特征为多腔米色脂肪细胞的形成。迄今为止，白色脂肪组织内介导产热重塑的全套寒冷响应细胞仍未被完全阐明。本研究证实，体内不同的血管周围PDGFRb+脂肪细胞前体细胞（adipocyte precursor cell, APC）亚群对寒冷刺激的敏感性存在显著差异。仅1天的寒冷暴露即可在DPP4+ PDGFRb+ APC中引发显著的转录组变化，而已定向分化的DPP4- PDGFRb+前脂肪细胞的响应程度则相对微弱。该适应过程涉及β肾上腺素能受体（beta-adrenergic receptor）介导的促产热细胞因子白细胞介素33（interleukin 33, IL-33）表达上调。在成年小鼠的腹股沟白色脂肪组织中，DPP4+ PDGFRb+细胞是IL-33的唯一来源。在寒冷暴露起始阶段，于PDGFRb+细胞中进行多西环素诱导性Il33敲除，可显著削弱白色脂肪组织的产热重塑过程，且不会直接影响脂肪细胞前体细胞本身的分化能力。综上，本研究揭示了成年小鼠白色脂肪组织中存在一类寒冷响应的祖细胞亚群，并阐明其可通过分泌免疫因子调控组织可塑性。整体实验设计：本研究采用批量RNA测序（bulk RNA-seq）技术，分析分别经溶剂（磷酸盐缓冲液，phosphate-buffered saline, PBS）或10mM异丙肾上腺素（isoproterenol）处理4小时的原代培养小鼠腹股沟白色脂肪组织DPP4阴性（DPP4_neg）与DPP4阳性（DPP4_pos）脂肪细胞前体细胞的基因表达谱。