Estrogen prevents age-dependent beige adipogenesis failure through NAMPT-controlled ER stress pathway

Thermogenic beige adipocytes are recognized as potential therapeutic targets for combating metabolic diseases. However, the metabolic advantages they offer are compromised with aging. Here, we show that treating mice with estrogen (E2), a hormone that decreases with age can counteract the age-related decline in beige adipogenesis when exposed to cold temperature, while concurrently enhancing energy expenditure and improving glucose tolerance in mice. Mechanistically, we find that nicotinamide phosphoribosyl transferase (NAMPT) plays a pivotal role in facilitating the formation of E2-induced beige adipocytes, which subsequently suppresses the onset of age-related ER stress. Furthermore, we found that targeting NAMPT signaling, either genetically or pharmacologically, can restore the formation of beige adipocytes by increasing the number of perivascular adipocyte progenitor cells. Conversely, the absence of NAMPT signaling prevents this process. Together, our findings shed light on the mechanisms regulating the age-dependent impairment of beige adipocyte formation and underscore the E2-NAMPT-controlled ER stress pathway as a key regulator of this process.

脂解性米色脂肪细胞被公认为对抗代谢性疾病的治疗靶点。然而，它们随年龄增长所提供的代谢优势受到了损害。本研究中，我们揭示了使用雌二醇（E2）——一种随年龄增长而减少的激素——治疗小鼠，可以逆转小鼠在冷暴露条件下米色脂肪生成的年龄相关性下降，同时增强能量消耗并改善小鼠的葡萄糖耐量。从机制上讲，我们发现烟酰胺磷酸核糖转移酶（NAMPT）在促进E2诱导的米色脂肪细胞形成中起着关键作用，进而抑制与年龄相关的内质网应激的发生。此外，我们发现通过遗传学或药理学靶向NAMPT信号通路，可以恢复米色脂肪细胞的形成，通过增加血管周围脂肪祖细胞的数量来实现。相反，NAMPT信号通路的缺失则阻止了这一过程。总之，我们的研究结果揭示了调节米色脂肪细胞形成年龄依赖性损害的机制，并强调了E2-NAMPT调控的内质网应激通路作为这一过程的关键调节因子。