Systemic metabolic benefits of 17α-estradiol are not exclusively mediated by ERα in glutamatergic or GABAergic neurons

• DOI: 10.1007/s11357-024-01192-2
• Publication Date: 2024-05-22T12:01:36Z
• Authors: Celine Camon; Mel Prescott; Christine Neyt; Caroline Decourt; Michael B. Stout; Rebecca E. Campbell; Michael Garratt
• Keywords: Male; Mice, Knockout; Neurons; 0301 basic medicine; Estradiol; Vesicular Inhibitory Amino Acid Transport Proteins; Arcuate Nucleus of Hypothalamus; Estrogen Receptor alpha; Glutamic Acid; Diet, High-Fat; Mice, Inbred C57BL; Mice; 03 medical and health sciences; Vesicular Glutamate Transport Protein 2; Animals; Original Article; Female; GABAergic Neurons

Abstract 17α-Estradiol (17αE2), a less-feminising enantiomer of 17β-estradiol, has been shown to prolong lifespan and improve metabolic health in sex-specific manner male, but not female mice. Recent studies have demonstrated the pivotal role estrogen receptor α (ERα) mediating effects 17αE2 on health. However, specific tissues and/or neuronal signalling pathways that acts through remain be elucidated. ERα expression glutamatergic GABAergic neurons (principal excitatory inhibitory respectively) hypothalamus is essential for estradiol signalling. Therefore, we hypothesised knocking out from one these populations would attenuate established beneficial male mice exposed high fat diet. To test this hypothesis used two brain KO models, targeting either or (Vglut2/Vgat-ERαKO). We show both models exhibit strong reduction arcuate nucleus hypothalamus, control centre regulation. Deletion significantly diminished effect body weight relative controls, although animals still benefits with treatment. The response was unaffected by deletion neurons. Our results support benefit treatment protection against dysfunction, do depend exclusive persist when strongly reduced hypothalamus.