Targeting the Adipose-Brain Axis: Adipokines as Key Modulators of Cognitive Dysfunction

Adipose tissue is an active endocrine organ that secretes adipokines capable of modulating brain function through metabolic, inflammatory, vascular, and neurotrophic pathways. Emerging evidence suggests that dysregulated adipokine signaling contributes to cognitive decline and neurodegeneration by impairing neuronal energy metabolism, mitochondrial function, insulin signaling, and synaptic plasticity, while amplifying oxidative stress and neuroinflammation. Therefore, this review aimed to summarize and discuss the potential roles of adipokines in brain health, particularly cognitive function, based on findings from preclinical and clinical studies.

The search strategy incorporated combinations of keywords and MeSH terms, including: "adipokine*", "leptin", "adiponectin", "resistin", "brain", "cognition", "cognitive decline", "dementia", "Alzheimer's disease", "aging", and "metabolic dysfunction".

Preclinical studies demonstrate the neuroprotective effects of adipokines such as leptin, adiponectin, and C1q/TNF-Related Protein-3 (CTRP3), which act through AMPK, PI3K/Akt, sirtuin, and anti-inflammatory signaling pathways to preserve neuronal survival and cognitive function. In contrast, adipokines including resistin, Dipeptidyl Peptidase-4 (DPP-4), Angiopoietin-like protein 4 (ANGPTL4), and visfatin may exacerbate neurodegeneration by promoting insulin resistance, amyloidogenic processing, mitochondrial dysfunction, oxidative stress, and chronic inflammation. However, clinical studies in aging populations have reported paradoxical associations between elevated circulating adipokine levels and worse cognitive outcomes, potentially reflecting compensatory upregulation, adipokine resistance, altered body composition, or age-related metabolic dysregulation.

This review highlights mechanistic and clinical evidence supporting adipokines as promising biomarkers and therapeutic targets for modulating the adipose-brain axis to prevent or slow cognitive decline.