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

  • Int Immunopharmacol. 2026 Jul 15:181:116728. doi: 10.1016/j.intimp.2026.116728.
Jinlong Chang  1 ,  Wenhui Zhu  2 ,  Tianxiang Li  3 ,  Dan Cui  4 ,  Haier Xie  5 ,  Zi Zhu  5 ,  Weifen Li  6
Affiliations
  • 1. Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Dali University, Dali 671003, China.
  • 2. Department of Laboratory Medicine, Guangdong Provincial Key Laboratory of Precision Medical Diagnostics, Guangdong Engineering and Technology Research Center for Rapid Diagnostic Biosensors, Guangdong Provincial Key Laboratory of Single-Cell and Extracellular Vesicles, Nanfang Hospital, Southern Medical University, Guangzhou 510000, China.
  • 3. State Key Laboratory of Oncogenomics, School of Chemical Biology and Biotechnology, Peking University Shenzhen Graduate School, Shenzhen 518000, China.
  • 4. Department of Surgical Nursing, School of Nursing, Dali University, Dali 671003, China.
  • 5. School of Pharmacy, Shenzhen University Medical School, Shenzhen University, Shenzhen 518060, China.
  • 6. School of Pharmacy, Shenzhen University Medical School, Shenzhen University, Shenzhen 518060, China. Electronic address: [email protected].
PMID: 42048734 DOI: 10.1016/j.intimp.2026.116728
Abstract

Aim: 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.

Methods: 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.

Results: 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.

Conclusion: 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.

Keywords
AdipoRon; Adiponectin receptor 2; Depression; Interleukin-10; Microglial polarization.
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