Adipokines at the Metabolic–Brain Interface: Therapeutic Modulation by Antidiabetic Agents and Natural Compounds in Alzheimer’s Disease

Abstract

The parallel global increase in obesity and Alzheimer’s disease (AD) underscores an urgent public health challenge, with converging evidence indicating that metabolic dysfunction strongly contributes to neurodegeneration. Obesity is now recognized not only as a systemic metabolic condition but also as a modifiable risk factor for AD, acting through mechanisms such as chronic low-grade inflammation, insulin resistance, and adipose tissue dysfunction. Among the molecular mediators at this interface, adipokines have emerged as pivotal regulators linking metabolic imbalance to cognitive decline. Adipokines are hormone-like proteins secreted by adipose tissue, including adiponectin, leptin, and resistin, that regulate metabolism, inflammation and can influence brain function. Resistin, frequently elevated in obesity, promotes neuroinflammation, disrupts insulin signaling, and accelerates β-amyloid (Aβ) deposition and tau pathology. Conversely, adiponectin enhances insulin sensitivity, suppresses oxidative stress, and supports mitochondrial and endothelial function, thereby exerting neuroprotective actions. The imbalance between resistin and adiponectin may shift the central nervous system toward a pro-inflammatory and metabolically compromised state that predisposes to neurodegeneration. Beyond their mechanistic relevance, adipokines hold translational promise as biomarkers for early risk stratification and therapeutic monitoring. Importantly, natural compounds, including polyphenols, alkaloids, and terpenoids, have shown the capacity to modulate adipokine signaling, restore metabolic homeostasis, and attenuate AD-related pathology in preclinical models. This positions adipokines not only as pathogenic mediators but also as therapeutic targets at the intersection of diabetes, obesity, and dementia. By integrating mechanistic, clinical, and pharmacological evidence, this review emphasizes adipokine signaling as a novel axis for intervention and highlights natural compound-based strategies as emerging therapeutic approaches in obesity-associated AD. Beyond nutraceuticals, antidiabetic agents also modulate adipokines and AD-relevant pathways. GLP-1 receptor agonists, metformin, and thiazolidinediones tend to increase adiponectin and reduce inflammatory tone, while SGLT2 and DPP-4 inhibitors exert systemic anti-inflammatory and hemodynamic benefits with emerging but still limited cognitive evidence. Together, these drug classes offer mechanistically grounded strategies to target the adipokine–inflammation–metabolism axis in obesity-associated AD. © 2025 by the authors.