Modulating fatty acid signaling to restore allopregnanolone balance: A novel strategy for anxiety disorders

Anxiety disorders, affecting up to 28 % of individuals globally, remain
poorly treated, necessitating novel therapeutic targets. Here, we identify
Elovl6, a key fatty acid elongase enriched in the human cerebral cortex,
as a critical regulator of anxiety-like behaviors. Chronic stress
downregulated Elovl6 in the prefrontal cortex (PFC), while Elovl6 knockout
(KO) mice exhibited heightened anxiety-like behaviors, including reduced
open-arm exploration in the elevated plus maze, increased compulsive
grooming, and impaired nest-building, without affecting depression-related
phenotypes. Mechanistically, Elovl6 deficiency disrupted brain lipid
homeostasis, increasing palmitic acid (PA, C16:0) while decreasing oleic
acid (OA, C18:1) and linoleic acid (LA, C18:2), leading to suppressed
PPARα expression in astrocytes and reduced allopregnanolone (Allo) levels.
Unsaturated fatty acids (OA/LA) or the PPARα agonist GW7647 reversed these
deficits, restoring Allo production and alleviating anxiety-like behaviors
in Elovl6-KO mice. Our findings reveal a novel Elovl6-fatty
acid-PPARα-Allo axis in anxiety pathophysiology and propose lipid
metabolism modulation as a promising therapeutic strategy.