Significance: The global obesity epidemic is a significant risk factor for chronic metabolic diseases. Iron, an essential micronutrient involved in numerous biological processes, exhibits a dual role in health and disease. Understanding the mechanistic interplay between iron metabolism and adipocytes is crucial for elucidating the pathogenesis of obesity. Recent Advances: Emerging evidence indicates that iron plays a key role in adipose tissue physiology, and its dysregulation contributes substantially to obesity pathogenesis. Within adipocytes, iron exerts multifaceted effects, influencing lipid metabolism, differentiation, thermogenic capacity, secretory function, mitochondrial activity, and insulin sensitivity. Conversely, the metabolic status of adipose tissue reciprocally affects systemic iron homeostasis. Goal of Review: This review underscores the phenomenon of iron dysregulation in obesity. It examines the cellular mechanism describing iron demand and its dysregulation across adipose tissue subtypes. Following, it explores the functional pathology connecting iron imbalance to impaired energy metabolism, thermogenesis capacity, immune modulation, and secretion activity in adipose tissue, as well as iron-related oxidative stress, ferroptosis, heme toxicity, and cellular senescence within adipocytes in obesity. Then, it expands to the systemic level, highlighting the interorgan crosstalk in iron homeostasis, particularly among the liver, gut, and adipose tissue. Finally, it discusses the therapeutic strategies targeting iron homeostasis regulation to alleviate obesity and its related complications. Future Direction: Despite advancements, questions remain regarding depot-specific iron regulation and its relationship with metabolic dysfunction. Future studies should employ tissue-specific genetic models, well-designed human trials, and multiomics approaches to establish causality and translate the findings into targeted iron-modulating therapies for obesity. Antioxid. Redox Signal. 00, 000–000.
Wang et al. (Thu,) studied this question.