The aryl hydrocarbon receptor (AhR), a ligand-activated transcription factor traditionally studied for its role in xenobiotic metabolism, has gained increasing attention for its involvement in metabolic regulation. In adipocytes and lipid metabolism, AhR emerges as both a “friend and foe,” exerting complex and sometimes opposing effects on obesity development and progression.
Activation of AhR influences adipogenesis, lipid storage, and energy homeostasis. On one hand, AhR activation can impair adipocyte differentiation by disrupting key regulators such as PPARγ and C/EBPα, leading to altered fat cell development. This effect may reduce lipid accumulation, suggesting a protective role against obesity. Additionally, AhR activation has been linked to the modulation of inflammatory pathways, potentially curbing the low-grade chronic inflammation often associated with adipose tissue expansion.
Conversely, chronic AhR activation, particularly through exposure to environmental pollutants such as dioxins and polychlorinated biphenyls (PCBs), has been associated with metabolic dysfunction. Persistent AhR signaling can promote insulin resistance, disrupt lipid metabolism, and exacerbate adipose tissue inflammation. In such contexts, AhR contributes to the pathogenesis of obesity and its comorbidities, including type 2 diabetes and cardiovascular disease.
Importantly, emerging evidence suggests that the impact of AhR may depend on the nature of its ligands. Endogenous ligands derived from diet or microbiota may have beneficial effects by modulating lipid metabolism and maintaining energy balance, while exogenous toxic ligands often trigger detrimental metabolic outcomes.
Thus, AhR represents a double-edged sword in adipocyte biology and obesity. Understanding the ligand-specific and context-dependent actions of AhR may open novel therapeutic avenues, including selective AhR modulators designed to harness its beneficial effects while minimizing harmful consequences.