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

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.