Obesity, a global health crisis, is widely known to disrupt metabolic and physiological functions across multiple organ systems. While its detrimental effects on cardiovascular health, liver function, and insulin sensitivity have been extensively explored, emerging research now shines light on a less understood consequence of obesity: impaired intestinal regeneration. A groundbreaking study led by Liu et al., published in Nature Metabolism, uncovers a novel molecular pathway linking adipose tissue dysfunction in obesity to compromised gut repair, involving the adipokine adipocyte fatty acid-binding protein (AFABP) and iron metabolism in intestinal stem cells (ISCs).
The gut epithelium is a dynamic and rapidly renewing tissue, relying heavily on the continuous proliferation and differentiation of ISCs to maintain barrier integrity and facilitate repair after injury. Disruptions in ISC function can lead to chronic intestinal disorders, including inflammatory bowel diseases. Although obesity-induced systemic inflammation is known to impact gut health, the intrinsic molecular mechanisms by which obesity curtails the intestine’s regenerative potential have remained elusive until now.
Central to this new discovery is AFABP, an adipocyte-derived fatty acid-binding protein that facilitates intracellular transport of lipids and functions as an adipokine influencing systemic metabolic regulation. Liu and colleagues found that AFABP secretion is markedly increased during obesity. Uniquely, their work demonstrates that AFABP directly interacts with plasma transferrin—the primary iron transport protein in the circulation—resulting in dysregulated iron uptake by ISCs.
This aberrant iron accumulation within ISCs produces a cascade of deleterious cellular consequences. Iron, while essential for numerous enzymatic processes, can catalyze the formation of reactive oxygen species via Fenton chemistry, inciting oxidative damage. More specifically, excessive intracellular iron disturbs the homeostasis of peroxisomes, organelles critical for lipid metabolism and reactive oxygen species detoxification. The disrupted peroxisomal function interferes with proper ISC differentiation pathways, fundamentally impeding the generation of mature epithelial cell lineages crucial for effective gut repair.
The authors employed a multifaceted approach combining obesity mouse models, genetically engineered AFABP overexpression, and in vivo colitis assays to unravel this intricate network. In obese mice, elevated circulating AFABP was tightly correlated with increased iron deposition in intestinal crypts where ISCs reside. Introducing AFABP overexpression specifically in adipocytes of lean mice was sufficient to replicate the ISC iron overload and impaired differentiation, underscoring AFABP’s causative role.
Furthermore, the research explored therapeutic avenues targeting this newly identified adipose-gut axis. Genetic deletion of AFABP or pharmacological inhibition using selective AFABP inhibitors substantially ameliorated colitis severity in obese animals. Similarly, administering iron chelators to reduce ISC iron overload or activating peroxisomal function restored ISC differentiation capacity and accelerated mucosal healing, highlighting the potential clinical relevance of modulating iron metabolism and peroxisome biology in gut regenerative medicine.
These findings profoundly advance our understanding of the molecular crosstalk between adipose tissue and the intestinal stem cell niche, revealing obesity-induced AFABP as a pivotal mediator of gut regenerative dysfunction. The work emphasizes the critical role of iron homeostasis within ISCs, linking metabolic disturbances caused by obesity not only to systemic complications but also to local impairment of tissue repair mechanisms.
Mechanistically, the study elucidates that AFABP binds to transferrin in the plasma, facilitating an abnormal increase in iron delivery to ISCs. This excess iron burdens the peroxisomal machinery, which hampers the differentiation into specialized epithelial cells like Paneth and goblet cells, known to be instrumental in maintaining intestinal barrier function and immune regulation. The resulting compromised epithelial regeneration creates a vulnerable milieu for prolonged inflammation and worsens outcomes in colitis models.
By dissecting the molecular underpinnings of how obesity instigates intestinal repair dysfunction, Liu et al. not only identify AFABP as a key pathological factor but also propose a conceptual framework where adipokines can orchestrate stem cell niche environments through metabolic intermediates. This paradigm shift could stimulate novel therapeutic strategies targeting adipose tissue-derived signals to counteract obesity-associated intestinal disorders.
Importantly, the translational implications of these insights extend beyond obesity. Given iron dysregulation and impaired peroxisome function are implicated in diverse gastrointestinal diseases, the elucidated pathway may have broader relevance in chronic inflammatory and degenerative gut pathologies. Future clinical investigations targeting AFABP signaling and ISC iron modulation might pave the way for innovative interventions to promote intestinal healing in obese patients suffering from inflammatory bowel disease and other gut injuries.
In summary, Liu and colleagues reveal a previously uncharted axis linking obesity, adipokine secretion, iron overload, and peroxisomal dysfunction in intestinal stem cells to impaired gut repair. Their study not only deepens the mechanistic understanding of obesity-related organ pathology but also identifies novel targets amenable to therapeutic modulation. As obesity prevalence continues to rise globally, insights into such tissue-specific molecular mechanisms offer promising routes for precision medicine approaches aimed at restoring intestinal health in affected individuals.
This pivotal research underscores the complex consequences of systemic metabolic disease on local regenerative processes, highlighting how adipose tissue-derived factors can profoundly influence stem cell function and tissue homeostasis. With continued exploration, these findings might inspire a new class of treatments designed to counteract the adverse effects of obesity on the gut and potentially other rapidly renewing organs vulnerable to metabolic disturbances.
Overall, this study is a testament to the power of integrating metabolic biology, stem cell research, and immunology to uncover innovative pathways and therapeutic opportunities. The intricate relationship between AFABP, iron overload, and peroxisome-mediated ISC differentiation represents a critical nexus in obesity-impaired intestinal healing, a frontier that promises to reshape current approaches to managing obesity-associated intestinal disease and beyond.
Subject of Research: The molecular mechanism by which obesity influences intestinal stem cell function and gut repair, focusing on the role of adipocyte fatty acid-binding protein (AFABP) mediated iron homeostasis in intestinal stem cells.
Article Title: Obesity Impairs Gut Repair via AFABP-Mediated Iron Overload in Intestinal Stem Cells
Article References:
Liu, Z., Chen, Y., Yan, J. et al. Obesity impairs gut repair via AFABP-mediated iron overload in intestinal stem cells. Nat Metab (2026). https://doi.org/10.1038/s42255-025-01425-4
Image Credits: AI Generated
DOI: https://doi.org/10.1038/s42255-025-01425-4
Tags: adipocyte fatty acid-binding proteinadipokines and gut healthchronic intestinal disordersgut epithelium renewalintestinal stem cells functioniron overload in obesitymetabolic dysfunction in obesitymolecular pathways in obesityobesity and gut healthobesity and intestinal regenerationobesity-related health crisissystemic inflammation and gut repair
