Abstract
17 alpha-Estradiol (17 alpha E2), a less-feminising enantiomer of 17 beta-estradiol, has been shown to prolong lifespan and improve metabolic health in a sex-specific manner in male, but not in female mice. Recent studies have demonstrated the pivotal role of estrogen receptor alpha (ER alpha) in mediating the effects of 17 alpha E2 on metabolic health. However, the specific tissues and/or neuronal signalling pathways that 17 alpha E2 acts through remain to be elucidated. ER alpha expression in glutamatergic and GABAergic neurons (principal excitatory and inhibitory neurons respectively) in the hypothalamus is essential for estradiol signalling. Therefore, we hypothesised that knocking out ER alpha from one of these neuronal populations would attenuate the established beneficial metabolic effects of 17 alpha E2 in male mice exposed to a high fat diet. To test this hypothesis we used two established brain specific ER alpha KO models, targeting either glutamatergic or GABAergic neurons (Vglut2/Vgat-ER alpha KO). We show that both of these ER alpha KO models exhibit a strong reduction in ER alpha expression in the arcuate nucleus of the hypothalamus, a control centre for metabolic regulation. Deletion of ER alpha from GABAergic neurons significantly diminished the effect of 17 alpha E2 on body weight relative to controls, although these animals still show metabolic benefits with 17 alpha E2 treatment. The response to 17 alpha E2 was unaffected by ER alpha deletion in glutamatergic neurons. Our results support a benefit of 17 alpha E2 treatment in protection against metabolic dysfunction, but these effects do not depend on exclusive ER alpha expression in glutamatergic and GABAergic neurons and persist when ER alpha expression is strongly reduced in the arcuate nucleus of the hypothalamus.