Modulation of hepcidin synthesis: the core link in the bi-directional relationship between iron and obesity

Over the past five decades, clinical and experimental data have established that iron metabolism, lipid metabolism, and obesity are intricately linked and differentially influence one another through complex metabolic pathways. Iron dyshomeostasis is now recognized as a key modulator of lipid metabolism, with profound implications for obesity and related metabolic disorders. Likewise, lipid metabolism and obesity significantly impact iron absorption and recycling. Although this interplay between iron metabolism, lipid metabolism, and obesity is complex, modulation of hepcidin synthesis seems to be the core link between these variables. As the global prevalence of metabolic disorders continues to escalate, understanding their multifactorial etiology has become a public health priority. Emerging evidence highlights the dysregulation of lipid metabolism as a central driver in the onset and progression of these conditions, with iron metabolism playing a crucial regulatory role. This review explores the relationship between iron metabolism on one hand and lipid metabolism and obesity on the other with specific emphasis on the molecular mechanisms underlying this relationship. The review also explores the bi-directional relationship between iron metabolism and mitochondrial functions, mainly energy production. It concludes by outlining the pathophysiological consequences of disrupted iron metabolism, vis-a-vis lipid metabolism, obesity, and diabetes. By synthesizing current knowledge, this review aims to provide new insights that could guide the development of novel therapeutic strategies to manage obesity, diabetes, and related metabolic disorders.