Iron supplementation regulates the progression of high fat diet induced obesity and hepatic steatosis via mitochondrial signaling pathways [II]

Disruption of iron metabolism is closely related to metabolic diseases. Iron deficiency is frequently associated with obesity and hepatic steatosis. However, the effects of iron supplementation on obesity and energy metabolism remain unclear. Here we show that a high-fat diet supplemented with iron reduces body weight gain and hepatic lipid accumulation in mice. Iron supplementation was found to reduce mitochondrial morphological abnormalities and upregulate gene transcription involved in mitochondrial function and beta oxidation in the liver and skeletal muscle. In both these tissues, iron supplementation increased the expression of genes involved in heme or iron–sulfur (Fe–S) cluster synthesis. Heme and Fe–S cluster, which are iron prosthetic groups contained in electron transport chain complex subunits, are essential for mitochondrial respiration. The findings of this study demonstrated that iron regulates mitochondrial signaling pathways—gene transcription of mitochondrial component molecules synthesis and their energy metabolism. Overall, the study elucidates the molecular basis underlying the relationship between iron supplementation and obesity and hepatic steatosis progression, and the role of iron as a signaling molecule. Male C57BL/6J mice of 6 weeks of age were fed with a control diet (Control;10% kcal fat), a high-fat diet (HF; 60% kcal fat), or a high-fat diet supplemented with 0.023% (w/w) sodium ferrous citrate (HF+SFC) for 15 weeks. Control diet (D12450B) contained 10 kcal% fat, 20 kcal% protein, and 70 kcal% carbohydrate, whereas the HF diet (D12492) contained 60 kcal% fat, 20 kcal% protein, and 20 kcal% carbohydrate (Research Diets, Inc., New Brunswick, NJ, USA). For each group, a mix of all sample cDNAs was used.

铁代谢紊乱与代谢性疾病密切相关。缺铁常与肥胖及肝脂肪变性（hepatic steatosis）相伴发生，然而补铁对肥胖与能量代谢的影响仍不明确。本研究发现，高脂饮食补充铁剂可降低小鼠体质量增长及肝脂质蓄积。研究显示，补铁能够减轻线粒体形态异常，并上调肝脏与骨骼肌中线粒体功能及β氧化（beta oxidation）相关基因的转录水平。在上述两种组织中，补铁均可提升参与血红素（heme）或铁硫簇（Fe–S cluster）合成的基因表达水平。血红素与铁硫簇作为电子传递链复合物亚基所含的铁辅基，对线粒体呼吸过程至关重要。本研究证实，铁可调控线粒体信号通路——即线粒体组分分子合成的基因转录及其能量代谢过程。综上，本研究阐明了补铁与肥胖及肝脂肪变性进展之间关联的分子基础，以及铁作为信号分子的作用。本研究选用6周龄雄性C57BL/6J小鼠，分别饲喂对照饮食（对照组：热量供能占比10%的脂肪）、高脂饮食（HF组：热量供能占比60%的脂肪），或添加0.023%（w/w）柠檬酸亚铁钠（sodium ferrous citrate, SFC）的高脂饮食（HF+SFC组），干预时长为15周。对照饲料（D12450B）的营养供能占比为：脂肪10%、蛋白质20%、碳水化合物70%；高脂饲料（D12492）的营养供能占比为：脂肪60%、蛋白质20%、碳水化合物20%，购自美国新泽西州新不伦瑞克市Research Diets, Inc.公司。每组均使用所有样本的互补脱氧核糖核酸（cDNA）混合液进行实验。