Central Feminization of Obese Male Mice Reduces Metabolic Syndrome

Metabolic syndrome encompasses a spectrum of conditions that increases the risk for cardiovascular and metabolic diseases. It is widely accepted that the sex hormone estrogen plays a protective metabolic role in premenopausal women, in part through central nervous system (CNS) mechanisms. However, most work to date has focused on the loss of estrogen in females (e.g., menopause). Interestingly, transgender individuals receiving feminizing gender affirming therapy (i.e., estrogen) are relatively protected from metabolic syndrome conditions, pointing to a role for CNS estrogen in the development of metabolic syndrome in men. Here, we show that estrogen signaling in the brain protects males from metabolic syndrome and obesity related complications. First, short-term CNS specific supplementation of low-dose 17-β-estradiol in diet-induced obese male mice resulted in a significant reduction in body weight in parallel with a decrease in food intake without alterations in energy expenditure. In conjunction, central supplementation of estrogen reduced visceral adiposity, including epididymal and abdominal regions, with slighter decreases in subcutaneous inguinal and thermogenic brown adipose tissue. Furthermore, central estrogen administration reduced the liver manifestation of metabolic syndrome including hepatomegaly and hepatic steatosis. Collectively, these findings indicate that a lack of estrogen action in the brain may predispose males to metabolic syndrome pathogenesis.