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Djulis Hull (Chenopodium formosanum) Ameliorates Iron Overload and Modulates Metabolic Functions in Obese Rats Fed Iron/Fat Enriched Diet
Other Title
Djulis Hull (Chenopodium formosanum) Ameliorates Iron Overload and Modulates Metabolic Functions in Obese Rats Fed Iron/Fat Enriched Diet
Type
thesis
Date Issued
2025-06-17
Author(s)
Amelia Faradina
Advisor
Subjects
系所名稱：保健營養學系博士班
Publisher
保健營養學系博士班
Description
學位別：博士
口試委員：許瑞芬; 蔡碧仁; 黃士懿; 蔡佳文; 張榮素
關鍵字：Iron overload、Obesity、Djulis hull、Hexacosanol、Iron metabolism
口試委員：許瑞芬; 蔡碧仁; 黃士懿; 蔡佳文; 張榮素
關鍵字：Iron overload、Obesity、Djulis hull、Hexacosanol、Iron metabolism
Abstract
Background
Dysmetabolic iron overload syndrome (DIOS) is associated with obesity and chronic low-grade inflammation. This iron dysregulation contributes to metabolic impairments, including insulin resistance, lipid imbalance, ferroptosis, and neurocognitive dysfunction. Despite the prevalence of obesity-related iron disorders, therapeutic strategies targeting both systemic and brain iron metabolism remain limited. Djulis hull (DH), a pseudocereal by-product rich in bioactive compounds such as hexacosanol, has shown potential anti-inflammatory, antioxidant, and metabolic regulatory properties. This study aimed to investigate the therapeutic potential of djulis hull (DH), and its major bioactive compound, in ameliorating iron overload and metabolic disturbances induced by iron/fat enriched diet in obese rat model.
Methods
Three interrelated studies were conducted using male Sprague-Dawley rats. In Study 1, rats received a control diet, high-fat diet (HFD), or HFD plus 2 g/kg ferric citrate, with or without DH supplementation (5%, 10%, or 15%) for 12 weeks. In Study 2, 10% DH was administered for 14 weeks under the same dietary conditions. In Study 3, following 8 weeks of DIOS induction, rats received intraperitoneal injections of hexacosanol-loaded nanoparticles—vehicle (MNP), untargeted (HNP), or macrophage-targeted (HMNP)—along with LPS to simulate inflammatory stress.
Results
Study 1: DH significantly improved hepatic iron regulation by suppressing IL-6 and hepcidin expression and upregulating ferroportin (Fpn). Hexacosanol and squalene were identified as the key bioactives enhancing Fpn expression via PHD2/HIF-2α and Keap1/Nrf2/HO-1 pathways. DH also reduced body weight and food intake, potentially through iron-mediated modulation of appetite hormones.
Study 2: DH restored hippocampal iron efflux and insulin signaling (IRS–PI3K–AKT), suppressed inflammation, and improved lipid metabolism by increasing MFSD2A and DHA-derived metabolites (DHEA). It downregulated ferroptosis markers (ACSL4, LPCAT3, NCOA4, 4-HNE) and upregulated protective factors (GPX4, SLC7A11, FSP1). DH also enhanced neurotrophic pathways (BDNF, p-CREB/CREB) and increased the abundance of beneficial gut bacteria, particularly Akkermansia, correlating with improved metabolic and cognitive outcomes.
Study 3: HMNPs provided superior neuroprotection compared to HNPs, effectively targeting macrophage-mediated inflammation and iron dysregulation. HMNP treatment significantly enhanced hippocampal iron export, reduced neuroinflammation, improved insulin sensitivity, lipid remodeling, and DHEA levels, and inhibited ferroptosis—demonstrating improved therapeutic outcomes through targeted delivery.
Conclusion
DH and hexacosanol, especially when delivered via macrophage-targeted nanoparticles, effectively alleviated DIOS-associated metabolic and neurocognitive impairments by modulating iron metabolism, ferroptosis, lipid remodeling, and the gut-brain axis—highlighting their potential as multi-target therapeutic strategies for obesity-related iron dysregulation.
Dysmetabolic iron overload syndrome (DIOS) is associated with obesity and chronic low-grade inflammation. This iron dysregulation contributes to metabolic impairments, including insulin resistance, lipid imbalance, ferroptosis, and neurocognitive dysfunction. Despite the prevalence of obesity-related iron disorders, therapeutic strategies targeting both systemic and brain iron metabolism remain limited. Djulis hull (DH), a pseudocereal by-product rich in bioactive compounds such as hexacosanol, has shown potential anti-inflammatory, antioxidant, and metabolic regulatory properties. This study aimed to investigate the therapeutic potential of djulis hull (DH), and its major bioactive compound, in ameliorating iron overload and metabolic disturbances induced by iron/fat enriched diet in obese rat model.
Methods
Three interrelated studies were conducted using male Sprague-Dawley rats. In Study 1, rats received a control diet, high-fat diet (HFD), or HFD plus 2 g/kg ferric citrate, with or without DH supplementation (5%, 10%, or 15%) for 12 weeks. In Study 2, 10% DH was administered for 14 weeks under the same dietary conditions. In Study 3, following 8 weeks of DIOS induction, rats received intraperitoneal injections of hexacosanol-loaded nanoparticles—vehicle (MNP), untargeted (HNP), or macrophage-targeted (HMNP)—along with LPS to simulate inflammatory stress.
Results
Study 1: DH significantly improved hepatic iron regulation by suppressing IL-6 and hepcidin expression and upregulating ferroportin (Fpn). Hexacosanol and squalene were identified as the key bioactives enhancing Fpn expression via PHD2/HIF-2α and Keap1/Nrf2/HO-1 pathways. DH also reduced body weight and food intake, potentially through iron-mediated modulation of appetite hormones.
Study 2: DH restored hippocampal iron efflux and insulin signaling (IRS–PI3K–AKT), suppressed inflammation, and improved lipid metabolism by increasing MFSD2A and DHA-derived metabolites (DHEA). It downregulated ferroptosis markers (ACSL4, LPCAT3, NCOA4, 4-HNE) and upregulated protective factors (GPX4, SLC7A11, FSP1). DH also enhanced neurotrophic pathways (BDNF, p-CREB/CREB) and increased the abundance of beneficial gut bacteria, particularly Akkermansia, correlating with improved metabolic and cognitive outcomes.
Study 3: HMNPs provided superior neuroprotection compared to HNPs, effectively targeting macrophage-mediated inflammation and iron dysregulation. HMNP treatment significantly enhanced hippocampal iron export, reduced neuroinflammation, improved insulin sensitivity, lipid remodeling, and DHEA levels, and inhibited ferroptosis—demonstrating improved therapeutic outcomes through targeted delivery.
Conclusion
DH and hexacosanol, especially when delivered via macrophage-targeted nanoparticles, effectively alleviated DIOS-associated metabolic and neurocognitive impairments by modulating iron metabolism, ferroptosis, lipid remodeling, and the gut-brain axis—highlighting their potential as multi-target therapeutic strategies for obesity-related iron dysregulation.