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.

Background: Obesity is a major health problem associated with increased comorbidities, which are partially triggered by inflammation. Proinflammatory macrophage infiltration in adipose tissue of individuals with obesity increases chronic inflammation. Obesity is associated with elevated plasma levels of saturated fatty acids, such as palmitic acid (PA), which promotes inflammation in vivo and in vitro. Infusions of Lampaya medicinalis Phil. (Verbenaceae) are used in the folk medicine of Northern Chile to counteract inflammation of rheumatic diseases. Hydroethanolic extract of lampaya (HEL) contains spectrophotometrically defined compounds that may contribute to the observed effect on inflammation. Methods: We evaluated the phytochemical composition of HEL by high-performance liquid chromatography coupled to diode array detection (HPLC-DAD) and liquid chromatography-electrospray ionization- tandem mass spectrometry (LC-ESI-MS/MS). We assessed whether the exposure to HEL affects PA-induced expression of proinflammatory factors in THP-1 macrophages. Results: HPLC-DAD and LC-ESI-MS/MS analyses showed the presence of considerable amounts of flavonoids in HEL. The PA-induced phosphorylation of the inflammatory pathway mediators IKK and NF-κB, as well as the elevated expression and secretion of proinflammatory cytokines (IL-6, TNF-α), were reduced in cells pre-exposed to HEL. Conclusion: These findings give new insights about the effect of HEL reducing IKK/NF-κB proinflammatory pathway, likely explained by the number of flavonoids contained in the extract. More studies would be needed to define the possible role of Lampaya as a preventive approach in subjects with obesity whose circulating PA might contribute to chronic inflammation.

Background: Aging and obesity are associated with insulin resistance (IR) and low-grade inflammation. Molecularly, IR is characterized by a reduction in glucose uptake and insulin signaling (IRS-1/Akt/AS160 pathway), while inflammation may result from upregulated NF-κB pathway after low Tyr-IκBα phosphorylation. Upregulated phosphatase activity of PTP1B is associated with impaired insulin signaling and increased inflammation. Plasma levels of palmitic acid (PA) are elevated in obesity, triggering inflammation and disruption of insulin signaling. Traditional medicine in Northern Chile uses oral infusions of Lampaya medicinalis Phil. (Verbenaceae) to treat inflammatory conditions. Significant amounts of flavonoids are found in the hydroethanolic extract of Lampaya (HEL), which may account for its biological activity. The aim of this work was to study the effect of HEL and PA on insulin signaling and glucose uptake as well as inflammatory marker expression in human adipocytes. Methods: We studied HEL effects on PA-induced impairment on insulin signaling, glucose uptake and inflammatory marker content in human SW872 adipocytes. HEL cytotoxicity was assessed in adipocytes at different concentrations (0.01 to 10 g/mL). Adipocytes were incubated or not with PA (0.4 mM, 24 h) with or without HEL (2 h pre-incubation), and then stimulated with insulin (10 min, 100 mM) or a vehicle. Phospho-IRS-1, phospho-Akt, phospho-AS160, phospho-NF-κB and phospho-IκBα, as well as protein levels of PTP1B, were assessed using Western blotting, and glucose uptake was evaluated using the 2-NBDG analogue. Results: At the assessed HEL concentrations, no cytotoxic effects were observed. PA decreased insulin-stimulated phospho-Akt and glucose uptake, while co-treatment with HEL increased such markers. PA decreased phospho-IRS-1 and phospho-Tyr-IκBα. On the other hand, incubation with HEL+PA decreased phospho-AS160 and phospho-NF-κB compared with cells treated with PA alone. Conclusion: Our results suggest a beneficial effect of HEL by improving PA-induced impairment on molecular markers of insulin signaling, glucose uptake and inflammation in adipocytes. Further studies are necessary to elucidate whether lampaya may constitute a preventive strategy for people whose circulating PA levels contribute to IR and inflammation during aging and obesity.