Fetuin-A Induced Suppression of PPAR Signaling: Molecular Insights and the Potential Regulatory Role of Fucosylation

Metabolic diseases are characterized by a complex interplay between metabolic dysregulation and chronic low-grade inflammation. Fetuin-A (FetA), a liver-derived hepatokine, has emerged as a key mediator linking these processes through its pro-inflammatory and insulin resistance-promoting effects. Accumulating evidence indicates that FetA not only serves as a biomarker but also actively contributes to disease pathogenesis by modulating multiple signaling pathways. In this review, we present an overview of the molecular mechanisms underlying FetA-induced suppression of peroxisome proliferator-activated receptor (PPAR) signaling, a central regulator of metabolic homeostasis. Emerging evidence suggests that FetA may promote Toll-like receptor 4 (TLR4)-mediated inflammation, activate nuclear factor kappa B (NF-κB) signaling, suppress key energy regulators such as Sirtuin 1 (SIRT1) and AMP-activated protein kinase (AMPK), and inhibit PPAR activity through Wnt and extracellular signal-regulated kinase (ERK) pathways. These interconnected mechanisms may contribute to impaired lipid metabolism, increased insulin resistance, and metabolic inflammation. Furthermore, we highlight the role of FetA glycosylation, particularly fucosylation, as a regulatory layer influencing its biological activity. Fucosylated FetA may more effectively activate TLR4 signaling and suppress PPAR activity, suggesting functional heterogeneity among glycoforms. Overall, the FetA–PPAR interaction may represent a key mechanistic link between metabolic inflammation and disease progression.