Estrogen Prevents Age-Related Decline in Beige Adipogenesis Through NAMPT Regulation

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. This work was supported by NIH grants K01 DK11177, R03 DK127149, R01 DK132398, and Pilot Support grant (P30DK020595) to Y.J., R01HL148756 to S.O., and R01DK123098 to P.X. This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.