Homeostatic regulation of energy balance is a precise tool concerned with maintaining a stable balance between energy intake and expenditure. Failure in the regulation of this physiological process gives rise to some disorders that are now considered public health problems with their reported increase in prevalence rate such as obesity and cachexia. obesity is caused by a chronic rise in energy consumption while cachexia results from a long-standing increase expended energy. Brown adipose tissue (BAT) thermogenesis is a crucial component of the energy balance equation. Recently, the hypothalamus and in particular, the ventromedial nucleus of the hypothalamus (VMH), vital role in the regulation of BAT activity has emerged. The hypothalamic AMP-activated protein kinase (AMPK), a sensor of energy levels, not only has a pivotal role in the regulation of both cellular and whole body energy balance but also is crucial in regulating BAT thermogenesis through the sympathetic nervous system (SNS).
The impact of sexual dimorphism on energy homeostasis and fat distribution is well established. Also, the influence of sex steroids on energy balance has been reported. Here, we demonstrate that estrogens and androgens have a major role in the modulation of energy balance through central actions. Central estradiol (E2) treatment inhibits AMPK in the VMH, leading to activation of thermogenesis in BAT in a feeding-independent manner. Moreover, fluctuations in E2 levels during estrous cycle also modulate this integrated physiological network. On the other hand, dihydrotestosterone (DHT)-treatment inhibited BAT thermogenesis so that the central effects of androgens on energy expenditure cannot be attributed to aromatization. Notably, central DHT-treatment demonstrated the ability to modulate the lean mass. Overall, these findings showed that E2 and DHT regulation of the VMH AMPK-SNS-BAT axis is an essential determinant of energy balance and suggest potential targets for treatment of both cachexia and obesity
