Estrogen counteracts age-related decline in beige adipogenesis through the NAMPT-regulated ER stress response.

Thermogenic beige adipocytes are recognized as potential therapeutic targets for combating metabolic diseases. However, the metabolic advantages that 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 found 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 endoplasmic reticulum (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.

The Notch-PDGFRß axis suppresses brown adipocyte progenitor differentiation in early post-natal mice.

De novo brown adipogenesis holds potential in combating the epidemics of obesity and diabetes. However, the identity of brown adipocyte progenitor cells (APCs) and their regulation have not been extensively explored. Here, through in vivo lineage tracing and mouse modeling, we observed that platelet-derived growth factor receptor beta (PDGFRß)+ pericytes give rise to developmental brown adipocytes but not to those in adult homeostasis. By contrast, T-box 18 (TBX18)+ pericytes contribute to brown adipogenesis throughout both developmental and adult stages, though in a depot-specific manner. Mechanistically, Notch inhibition in PDGFRß+ pericytes promotes brown adipogenesis by downregulating PDGFRß. Furthermore, inhibition of Notch signaling in PDGFRß+ pericytes mitigates high-fat, high-sucrose (HFHS)-induced glucose and metabolic impairment in mice during their development and juvenile phases. Collectively, these findings show that the Notch/PDGFRß axis negatively regulates developmental brown adipogenesis, and its repression promotes brown adipose tissue expansion and improves metabolic health.

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. Highlights: Estrogen restores beige adipocyte failure along with improved energy metabolism in old mice.Estrogen enhances the thermogenic gene program by mitigating age-induced ER stress.Estrogen enhances the beige adipogenesis derived from SMA+ APCs.Inhibiting the NAMPT signaling pathway abolishes estrogen-promoted beige adipogenesis.

The Notch-Pdgfrß axis suppresses brown adipocyte progenitor differentiation in early postnatal mice.

De novo brown adipogenesis holds potential in combating the epidemics of obesity and diabetes. However, the identity of brown adipocyte progenitor cells (APCs) and their regulation have not been extensively studied. Here through in vivo lineage tracing, we observed that PDGFRß+ pericytes give rise to developmental brown adipocytes, but not to those in adult homeostasis. In contrast, TBX18+ pericytes contribute to brown adipogenesis throughout both developmental and adult stages, though in a depot-specific manner. Mechanistically, Notch inhibition in PDGFRß+ pericytes promotes brown adipogenesis through the downregulation of PDGFRß. Furthermore, inhibition of Notch signaling in PDGFRß+ pericytes mitigates HFHS (high-fat, high-sucrose) induced glucose and metabolic impairment in both developmental and adult stages. Collectively, these findings show that the Notch/PDGFRß axis negatively regulates developmental brown adipogenesis, and its repression promotes brown adipose tissue expansion and improves metabolic health. Highlights: PDGFRß+ pericytes act as an essential developmental brown APC.TBX18+ pericytes contribute to brown adipogenesis in a depot-specific manner.Inhibiting Notch-Pdgfrß axis promotes brown APC adipogenesis.Enhanced postnatal brown adipogenesis improves metabolic health in adult stage.

Genetically prolonged beige fat in male mice confers long-lasting metabolic health.

A potential therapeutic target to curb obesity and diabetes is thermogenic beige adipocytes. However, beige adipocytes quickly transition into white adipocytes upon removing stimuli. Here, we define the critical role of cyclin dependent kinase inhibitor 2A (Cdkn2a) as a molecular pedal for the beige-to-white transition. Beige adipocytes lacking Cdkn2a exhibit prolonged lifespan, and male mice confer long-term metabolic protection from diet-induced obesity, along with enhanced energy expenditure and improved glucose tolerance. Mechanistically, Cdkn2a promotes the expression and activity of beclin 1 (BECN1) by directly binding to its mRNA and its negative regulator BCL2 like 1 (BCL2L1), activating autophagy and accelerating the beige-to-white transition. Reactivating autophagy by pharmacological or genetic methods abolishes beige adipocyte maintenance induced by Cdkn2a ablation. Furthermore, hyperactive BECN1 alone accelerates the beige-to-white transition in mice and human. Notably, both Cdkn2a and Becn1 exhibit striking positive correlations with adiposity. Hence, blocking Cdkn2a-mediated BECN1 activity holds therapeutic potential to sustain beige adipocytes in treating obesity and related metabolic diseases.