Objective

Estrogens play a pivotal role in energy balance control, by acting on its CNS receptors. It is generally assumed that the gonads are the main source of estradiol for these receptors. However, aromatase, the sole enzyme responsible for estradiol synthesis, is also present in the brain, and its role in energy balance remains largely unexplored.

Methods and Results

We identified high aromatase expression in the neurons of rat amygdala and investigated whether brain-derived estradiol, particularly within the amygdala, plays a role in energy balance and food reward control. Both whole brain chronic pharmacological inhibition of aromatase with a clinically utilized inhibitor, Letrozole, and a virogenetic approach to manipulate aromatase specifically in the amygdala were used in adult male and female rats, in conjunction with an array of measurements assessing feeding behavior and thermoregulation. Our results show that inhibition of brain aromatase results in increased food intake and body weight gain in females, but reduced food intake in males. This was driven by opposing effects on food preference for a high-fat diet. Amygdala aromatase knockdown was sufficient to increase feeding and body weight in lean and obese females, with increased visceral adiposity; effects not observed in males. Even in the absence of ovarian steroids, which already results in obesity, loss of amygdala aromatase further exacerbated weight gain and hyperphagia on an obesogenic diet. In females, hyperphagia was driven by increased meal size and increased food-motivated behavior, with increased preference for fat-rich but not sucrose-rich foods. Loss of amygdala aromatase also led to disrupted thermoregulation, with increased temperature in males but reduced in females, linked to alteration in brown adipose tissue thermogenesis.

Conclusions

Collectively, our data reveal that estradiol synthesis in the brain is necessary for body weight and feeding behavior control, as well as thermoregulation, in a sex specific manner. Our findings may have translational and clinical relevance, as aromatase inhibitors are widely used in the clinic, and aromatase has recently been found in the human amygdala.