Estradiol Regulates Brown Adipose Tissue Thermogenesis via Hypothalamic AMPK

Summary Estrogens play a major role in the modulation of energy balance through central and peripheral actions. Here, we demonstrate that central action of estradiol (E2) inhibits AMP-activated protein kinase (AMPK) through estrogen receptor alpha (ERα) selectively in the ventromedial nucleus of the hypothalamus (VMH), leading to activation of thermogenesis in brown adipose tissue (BAT) through the sympathetic nervous system (SNS) in a feeding-independent manner. Genetic activation of AMPK in the VMH prevented E2-induced increase in BAT-mediated thermogenesis and weight loss. Notably, fluctuations in E2 levels during estrous cycle also modulate this integrated physiological network. Together, these findings demonstrate that E2 regulation of the VMH AMPK-SNS-BAT axis is an important determinant of energy balance and suggest that dysregulation in this axis may account for the common changes in energy homeostasis and obesity linked to dysfunction of the female gonadal axis.
Graphical Abstract
Highlights • Central estradiol (E2) promotes negative energy balance • Central E2 increases thermogenic sympathetic nerve activity • Central E2 inhibits AMPK, specifically in the VMH, through ERα • The VMH AMPK-SNS-BAT axis mediates the central actions of E2 on energy balance
Estrogens play a major role in the regulation of body weight. Martínez de Morentin and colleagues show that estradiol (E2), acting through estrogen receptor alpha, selectively inhibits the energy sensor AMPK in the brain hypothalamic ventromedial nucleus, leading to activation of thermogenesis in brown adipose tissue.