Changes in nucleus accumbens gene expression accompany sex specific suppression of voluntary physical activity in aromatase knockout mice
Aromatase is the rate-limiting enzyme in the conversion of testosterone to estrogen and is highly conserved across species. Post-menopause, the aromatase enzyme (locally expressed in adipose tissue, bone, breast tissue, and brain) is the primary source of estradiol in females, as well as the sole source of estradiol in males throughout the lifespan. Notably, secondary sources of estrogens (e.g. phytoestrogens, 27- hydroxycholesterol) also bind estrogen receptors alpha and beta, but with lower affinity (Starkey, Li et al. 2018, Vieira-Potter, Cross et al. 2018). Loss of estrogen contributes to metabolic dysfunction, primarily in women, resulting in obesity and insulin resistance. Pharmacologic downregulation of aromatase activity via aromatase inhibitors is commonly used in males and females for treatment of diseases associated with estrogen (e.g. short stature in pubertal boys or adjuvant hormone therapy in postmenopausal breast cancer). However, the implications of suppression of aromatase on neurologic functions, such as cognition, memory, and mood, and even motivation for physical activity in the nucleus accumbens (NAc) brain region via alterations in dopamine signaling, are not entirely clear.