UCLA

Obesity is a complex and prevalent condition in the United States and is associated with higher rates of mortality driven by cardiovascular disease, type 2 diabetes, and certain types of cancer. Prior research showed that expression of adipose tissue Esr1, which encodes estrogen receptor alpha (ERα), inversely associates with adiposity in both humans and rodents. Studies of an adipose-specific Esr1 knockout mouse model showed that ERα regulates energy homeostasis in white adipose tissue (WAT) and brown adipose tissue (BAT) via coordinated control of mitochondrial DNA replication and fission-fusion-mitophagy dynamics. However, the molecular mechanisms of the metabolic-protective role of ERα in adipose tissue, specifically in BAT, are not clear. Herein, we investigated the metabolic role of ERα by overexpressing Esr1 through both female and male adipose-specific ERα transgenic mice. We found that overexpression of Esr1 in adipose tissue of female mice ameliorated high-fat diet-feeding-induced weight gain and elevated core body temperatures. Further examination of male mice with adipose overexpression of ERα showed that the protective role of ERα is hormone dependent. Elevated core body temperatures did not coordinate with Ucp1 expression, a key regulator of thermogenesis, indicating that ERα regulates thermogenesis in BAT via Ucp1-independent action. Moreover, studies showed that estradiol (E2) elevated calcium cycling, and E2-ERα transcriptionally regulates expression of calcium transporter Serca2b in primary brown adipocytes as a means of thermogenesis. Together, we found a novel role of ERα in regulating a noncanonical thermogenesis pathway enhancing calcium cycling via the calcium transporter Serca2b in BAT.