AdipoRon alleviates depression-like behaviors in mice by activating AdipoR2-JAK1-STAT3 pathway in microglia

Major depressive disorder (MDD) is a disabling psychiatric disease featuring altered adiponectin signaling, evidenced by changes in peripheral adiponectin levels and receptor activation-both potentially predictive of treatment response. While adiponectin's therapeutic role in MDD is established, specific molecular mechanisms, particularly relating to neuroinflammation, remain unclear.

Used a chronic restraint stress (CRS) mouse model treated with AdipoRon (adiponectin receptor agonist). In vitro adiponectin receptor 2 (AdipoR2) knockdown in BV2 microglia and genetic AdipoR2 ablation in mice were performed. KEGG analysis compared serum metabolites from the patients with depression and controls.

AdipoRon alleviated depressive-like behaviors in CRS mice, promoting hippocampal microglial polarization to the anti-inflammatory M2 phenotype and selectively increasing hippocampal interleukin-10 (IL-10). AdipoR2 knockdown in BV2 cells altered cytokine/protein profiles. AdipoRon activated hippocampal AdipoR2 expression and modulated JAK1/STAT1/STAT3 phosphorylation in CRS mice. AdipoR2 knockout induced depression-like behaviors. KEGG analysis revealed significant alterations in adiponectin-associated lipid metabolism pathways (glycerophospholipid/glycerolipid metabolism, pentose phosphate pathway) in MDD patients.

AdipoR2 activation mediates AdipoRon's antidepressant effects via AdipoR2-dependent hippocampal microglial M2 polarization, enhanced IL-10, downstream JAK/STAT signaling, and systemic lipid metabolic adaptations. This supports AdipoRon as a promising therapeutic for stress-related depression.