Estrogen Counteracts Age-Related Decline in Beige Adipogenesis Through the NAMPT-Regulated ER Stress Response

Reversal of Beige Fat Decline by Estrogen

Through NAMPT-Regulated Endoplasmic Reticulum Stress Response

Abstract: Brown adipocytes are valued for their potential therapeutic effects against metabolic diseases. However, the metabolic advantages provided by these cells deteriorate with age. Our research shows that treating mice with estrogen (E2), a hormone that decreases with age, can reverse age-related decline in beige fat formation (generation of beige adipocytes), enhance energy expenditure in cold environments, and improve glucose tolerance in mice. We found that nicotinamide phosphoribosyltransferase (NAMPT) plays a crucial role in E2-induced beige adipocyte formation and subsequently inhibits the onset of age-related endoplasmic reticulum (ER) stress. Additionally, our findings reveal the disrupted mechanisms regulating age-related beige adipocyte formation and emphasize the E2-NAMPT controlled ER stress pathway as a key regulator in this process.

Background: Obesity and diabetes have become major health concerns in the elderly population. Hence, alleviating obesity and its complications is an important medical need. Mammals have three different types of adipose tissue: white, brown, and beige. White adipose tissue is used for storing excess energy; whereas brown adipose tissue and the beige adipose tissue discovered in the past decade are involved in non-shivering thermogenesis to maintain body temperature. Beige adipose tissue has gradually become a new cellular target for combating obesity and diabetes, but its activity declines with age. Moreover, it is well known that aging-induced beige fat decline involves multiple processes and pathways, such as cellular senescence of adipose precursor cells. However, the molecular mechanisms underlying age-related beige adipocyte dysfunction remain unclear.

Key Points: 1. Estrogen reversed the age-related decline in beige fat formation, enhancing energy expenditure and glucose tolerance in mice. 2. Nicotinamide phosphoribosyltransferase (NAMPT) is crucial for E2-induced beige adipocyte formation and reduces age-related endoplasmic reticulum (ER) stress. 3. Targeting NAMPT signaling via genetic or pharmacological methods can restore beige adipocyte formation and potentially ameliorate metabolic damage caused by aging. 4. Further research shows that E2 can stimulate the differentiation of smooth muscle actin-positive precursor cells (sma+ apcs) into beige adipocytes, relying on NAMPT activity.

Significance: This research reveals the role of estrogen in countering age-related decline in beige adipocyte generation, advancing our understanding of energy metabolism and highlighting the E2/NAMPT/ER stress axis as a potential strategy for treating obesity. Intervening in this metabolic process provides new ideas for combating obesity and age-related issues.