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, to mice can counteract the aging- related decline in beige adipocyte formation when subjected to cold, while concurrently enhancing energy expenditure and improving glucose tolerance. Mechanistically, we find that nicotinamide phosphoribosyltranferase (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. In conclusion, our findings shed light on the mechanisms governing the age-dependent impairment of beige adipocyte formation and underscore the E2-NAMPT controlled ER stress as a key regulator of this process. HighlightsO_LIEstrogen restores beige adipocyte failure along with improved energy metabolism in old mice. C_LIO_LIEstrogen enhances the thermogenic gene program by mitigating age-induced ER stress. C_LIO_LIEstrogen enhances the beige adipogenesis derived from SMA+ APCs. C_LIO_LIInhibiting the NAMPT signaling pathway abolishes estrogen-promoted beige adipogenesis. C_LI