Estradiol Regulates Brown Adipose Tissue Thermogenesis via Hypothalamic AMPK

摘要

class="head no_bottom_margin" id="sec1title">IntroductionOvarian estrogens play a major role in the regulation of energy homeostasis (). Decreased levels of estradiol (E2) after menopause or ovariectomy (OVX) are also associated with hyperphagia, reduced energy expenditure, and weight gain (). In turn, E2 replacement therapy prevents OVX-induced obesity by decreasing feeding and increasing energy expenditure (). Likewise, hormone replacement therapy reverses the development of obesity and metabolic dysfunctions in postmenopausal women (). Studies have also suggested variations in meal size and body weight in rats depending on the stage of the estrous cycle (), as well as during pregnancy and lactation ().Genetic models of loss of function of estrogen receptors (ERs), which are widely expressed in the hypothalamus (), have demonstrated that mice with global or brain-specific targeted disruption of ER alpha (ERα) are obese, as a consequence of hyperphagia and hypometabolism (). Similarly, mice and patients deficient for the aromatase enzyme, which mediates the conversion of androgens to estrogens, develop obesity (). Interestingly, estrogens display a nucleus-specific action within the hypothalamus to modulate energy balance, particularly within the arcuate (ARC) and ventromedial (VMH) nuclei. VMH-specific delivery of adeno-associated viral vectors silencing ERα in mice and rats leads to marked obesity, impaired glucose tolerance, and reduced energy expenditure (). Of note, these genetic manipulations did not alter food intake, indicating that estrogens actions in the VMH modulate specifically energy expenditure. In keeping with this, female mice lacking ERα in hypothalamic steroidogenic factor-1 (SF1) neurons of the VMH exhibit reduced energy expenditure and brown adipose tissue (BAT)-mediated thermogenesis, leading to obesity, despite normal feeding (). In contrast, deletion of ERα in proopiomelanocortin (POMC) neurons of the ARC leads to hyperphagia without changes in energy expenditure (). Finally, concomitant deletion of ERα from both SF1 and POMC neurons recapitulates both phenotypes, causing hypometabolism, hyperphagia, and severe obesity ().Despite this evidence, the molecular and cellular events mediating E2-induced negative energy balance and BAT thermogenesis remain elusive. Thus, the aim of this study was to investigate the hypothalamic mechanism mediating E2-induced thermogenesis. We show that central E2 regulates BAT thermogenesis through ERα and activation of the sympathetic nervous system (SNS) by modulating hypothalamic AMP-activated protein kinase (AMPK), specifically in the VMH.