2. Academic Validation
  3. Adiponectin Signaling Ameliorates Cognitive Dysfunction in Type 2 Diabetic Mice by Activating the Hippocampal AdipoR2-PPARα/CREB Pathway

Adiponectin Signaling Ameliorates Cognitive Dysfunction in Type 2 Diabetic Mice by Activating the Hippocampal AdipoR2-PPARα/CREB Pathway

  • Mol Neurobiol. 2025 Nov 19;63(1):68. doi: 10.1007/s12035-025-05383-6.
Hongyan Gong 1 2,  Yanli Liu 2,  Liu Xia 2 3,  Bochao Niu 1,  Jian Kong 2 3,  Bin Wang 2,  Xu Lin 2,  Lin Lin 4,  Yanlin Bi 5
Affiliations

Affiliations

  • 1 MOE Key Laboratory for Neuroinformation, School of Life Science and Technology, University of Electronic Science and Technology of China, Chengdu, China.
  • 2 Department of Anesthesiology, Qingdao Municipal Hospital, Qingdao Hospital of Health and Rehabilitation Sciences University, Qingdao, China.
  • 3 School of Anesthesiology, Shandong Second Medical University, Weifang, China.
  • 4 Department of Anesthesiology, Qingdao Municipal Hospital, Qingdao Hospital of Health and Rehabilitation Sciences University, Qingdao, China. [email protected].
  • 5 Department of Anesthesiology, Qingdao Municipal Hospital, Qingdao Hospital of Health and Rehabilitation Sciences University, Qingdao, China. [email protected].
PMID: 41254427 DOI: 10.1007/s12035-025-05383-6
Abstract

Diabetes-Associated Cognitive Impairment (DACI) is a significant neurological complication of Type 2 Diabetes Mellitus (T2DM). This study investigates the role of the hippocampal Adiponectin (APN) system in DACI and the therapeutic potential of AdipoRon, an oral APN receptor agonist. Using a high-fat diet/streptozotocin-induced T2DM mouse model, we found that cognitive deficits were associated with a significant downregulation of hippocampal Adiponectin Receptor 2 (AdipoR2), which was predominantly localized to neurons. Oral AdipoRon administration (50 and 100 mg/kg/day for 2 weeks) reversed these cognitive impairments and improved metabolic parameters. Mechanistically, these benefits were linked to the upregulation of hippocampal AdipoR2, restoration of postsynaptic proteins (PSD95, GluA1), and attenuation of neuroinflammation, as evidenced by reduced microglial and astrocyte activation. Furthermore, AdipoRon activated the hippocampal PPARα/CREB signaling pathway. In vitro experiments using high-glucose-treated HT22 hippocampal neurons confirmed that AdipoRon's neuroprotective effects, including improved CREB phosphorylation and reduced oxidative stress, were mediated via a PPARα-dependent mechanism. In conclusion, our findings highlight hippocampal AdipoR2 dysregulation as a key factor in DACI and establish AdipoRon as a promising therapeutic agent that acts through the AdipoR2/PPARα/CREB pathway. This positions AdipoRon as a candidate for further investigation in the prevention and treatment of DACI.

Keywords

AdipoRon; Cognitive impairment; PPARα; Synaptic plasticity; Type 2 diabetes mellitus.

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