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.