Crosstalk Between Antioxidants and Adipogenesis: Mechanistic Pathways and Their Roles in Metabolic Health

Abstract

The interplay between oxidative stress and adipogenesis is a critical factor in the development of obesity and its associated metabolic disorders. Excessive reactive oxygen species (ROS) disrupt key transcription factors such as peroxisome proliferator-activated receptor gamma (PPARγ) and CCAAT/enhancer-binding protein alpha (C/EBPα), impairing lipid metabolism, promoting adipocyte dysfunction, and exacerbating inflammation and insulin resistance. Antioxidants, classified as endogenous (e.g., glutathione, superoxide dismutase, and catalase) and exogenous (e.g., polyphenols, flavonoids, and vitamins C and E), are pivotal in mitigating these effects by restoring redox balance and preserving adipocyte functionality. Endogenous antioxidants neutralize ROS and safeguard cellular structures; however, under heightened oxidative stress, these defenses are often insufficient, necessitating dietary supplementation. Exogenous antioxidants derived from plant-based sources, such as polyphenols and vitamins, act through direct ROS scavenging, upregulation of endogenous antioxidant enzymes, and modulation of key signaling pathways like nuclear factor kappa B (NF-κB) and PPARγ, reducing lipid peroxidation, inflammation, and adipocyte dysfunction. Furthermore, they influence epigenetic regulation and transcriptional networks to restore adipocyte differentiation and limit lipid accumulation. Antioxidant-rich diets, including the Mediterranean diet, are strongly associated with improved metabolic health, reduced obesity rates, and enhanced insulin sensitivity. Advances in personalized antioxidant therapies, guided by biomarkers of oxidative stress and supported by novel delivery systems, present promising avenues for optimizing therapeutic interventions. This review, "Crosstalk Between Antioxidants and Adipogenesis: Mechanistic Pathways and Their Role in Metabolic Health", highlights the mechanistic pathways by which antioxidants regulate oxidative stress and adipogenesis to enhance metabolic health.

Keywords: C/EBPα; PPARγ; adipogenesis; endogenous antioxidants; epigenetic mechanisms; insulin resistance; natural antioxidants; obesity; oxidative stress; personalized antioxidant therapies.

Figure 1

Mechanisms of antioxidant regulation on oxidative stress and transcription factors SREBP-1c, PPARγ, and C/EBPα. Natural antioxidants, including vitamin C, vitamin E, anthocyanins, quercetin, and resveratrol, directly or indirectly modulate these factors. Vitamin C and quercetin directly inhibit SREBP-1c, reducing lipid biosynthesis, while resveratrol activates PPARγ, enhancing anti-inflammatory responses. Endogenous antioxidants like SOD, GPx, ubiquinol, CoQ10, and GSH help maintain redox balance. CoQ10 and GSH directly activate PPARγ, while GPx and ubiquinol indirectly suppress SREBP-1c. Molecular structures of ubiquinone and ubiquinol demonstrate their roles in redox cycling, highlighting the essential function of antioxidants in metabolic regulation.

Figure 2

The balance between oxidative stress and antioxidant defenses in regulating FABP4 and adipogenesis. Oxidative stress (left), driven by ROS and inflammation (via NF-κB and cytokines like IFN-γ, TNF-α, and IL-6), suppresses transcription factors PPARγ and C/EBPα, leading to FABP4 dysregulation and impaired adipocyte function. Antioxidant defenses (right), including endogenous enzymes (GPx, SOD, catalase) and dietary antioxidants (e.g., resveratrol, curcumin), neutralize ROS, inhibit NF-κB, and restore transcription factor activity, normalizing FABP4 expression. FABP4 links these pathways, facilitating healthy adipogenesis by supporting lipid metabolism and adipocyte differentiation.