Department of Anaesthesiology, First Affiliated Hospital with Nanjing Medical University, Nanjing 210029, China.
Jiangsu Provincial Key Laboratory of Geriatrics, Department of Geriatrics, First Affiliated Hospital with Nanjing Medical University, Nanjing 210029, China.
Biochim Biophys Acta Mol Basis Dis. 2019 Jun 1;1865(6):1451-1459. doi: 10.1016/j.bbadis.2019.02.017. Epub 2019 Feb 22.
Browning of white adipose tissues (WAT) is critical for a variety of physiological and pathophysiological events. Given the limited understanding in molecular control of WAT browning, further research is needed. Heat shock protein A12A (HSPA12A) is a new member of multigene Hsp70 family. This study investigated the effect of HSPA12A on the browning of WAT. WAT Browning in mice was induced by cold exposure for 5 days. We observed that nuclear HSPA12A content was increased in WAT after cold exposure, while deficiency of HSPA12A (Hspa12a) promoted the cold-induced browning of WAT in mice compared to wild type (WT) littermates. Accordingly, Hspa12a mice showed attenuation of body temperature drop and increase of thermogenic gene expression compared to WT mice after cold exposure. However, in vitro experiments demonstrated that HSPA12A deficiency in primary white adipocytes did not affect their browning and thermogenic gene expression. Further loss- and gain-of-HSPA12A functional studies revealed that HSPA12A deficiency promoted whereas HSPA12A overexpression impeded M2 macrophage polarization. Importantly, the conditioned medium (CM) from Hspa12a bone marrow-derived macrophages (BMDMs) enhanced the browning of primary white adipocytes when compared to the CM from WT BMDMs. The data identified macrophage HSPA12A as a novel regulator of WAT browning through a paracrine mechanism. Targeting HSPA12A might provide meaningful advances for the management of browning-associated physiological events such as hypothermia adaptation and pathophysiological disorders such as obesity and cancer-related cachexia.
白色脂肪组织（WAT）的褐变对于多种生理和病理生理事件至关重要。鉴于对 WAT 褐变分子控制的了解有限，需要进一步研究。热休克蛋白 A12A（HSPA12A）是多基因 Hsp70 家族的新成员。本研究探讨了 HSPA12A 对 WAT 褐变的影响。通过冷暴露 5 天诱导小鼠 WAT 褐变。我们观察到冷暴露后 WAT 中核 HSPA12A 含量增加，而与野生型（WT）同窝仔相比，HSPA12A 缺乏（Hspa12a）促进了冷诱导的 WAT 褐变。因此，与 WT 小鼠相比，冷暴露后 Hspa12a 小鼠的体温下降幅度降低，产热基因表达增加。然而，体外实验表明，初级白色脂肪细胞中 HSPA12A 的缺乏并不影响其褐变和产热基因表达。进一步的 HSPA12A 缺失和过表达功能研究表明，HSPA12A 缺乏促进而 HSPA12A 过表达抑制 M2 巨噬细胞极化。重要的是，与 WT BMDM 的 CM 相比，来自 Hspa12a 骨髓来源巨噬细胞（BMDM）的 CM 增强了初级白色脂肪细胞的褐变。数据确定巨噬细胞 HSPA12A 是通过旁分泌机制调节 WAT 褐变的新调节因子。靶向 HSPA12A 可能为管理与褐变相关的生理事件（如体温适应）和病理生理障碍（如肥胖和癌症相关恶病质）提供有意义的进展。
