Moreno-Navarrete José María, Ortega Francisco, Rodríguez Amaia, Latorre Jèssica, Becerril Sara, Sabater-Masdeu Mònica, Ricart Wifredo, Frühbeck Gema, Fernández-Real José Manuel
Department of Diabetes, Endocrinology and Nutrition, Institut d'Investigació Biomèdica de Girona (IdIBGi), Hospital of Girona 'Dr Josep Trueta', Carretera de França s/n, 17007, Girona, Spain.
Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III (ISCIII), Spain, .
Diabetologia. 2017 May;60(5):915-926. doi: 10.1007/s00125-017-4228-0. Epub 2017 Feb 27.
AIMS/HYPOTHESIS: Iron excess in adipose tissue is known to promote adipose tissue dysfunction. Here, we aimed to investigate the possible role of haem oxygenase 1 (HMOX1) in iron excess-induced adipose tissue dysfunction.
Cross-sectionally, HMOX1 gene expression in subcutaneous and visceral adipose tissue was analysed in two independent cohorts (n = 234 and 40) in relation to obesity. We also evaluated the impact of weight loss (n = 21), weight gain (in rats, n = 20) on HMOX1 mRNA; HMOX1 mRNA levels during human adipocyte differentiation; the effects of inflammation and iron on adipocyte HMOX1; and the effects of HMOX1-induced activity on adipocyte mitochondrial respiratory function, glucose uptake and adipogenesis.
Adipose tissue HMOX1 was increased in obese participants (p = 0.01) and positively associated with obesity-related metabolic disturbances, and markers of iron accumulation, inflammation and oxidative stress (p < 0.01). HMOX1 was negatively correlated with mRNAs related to mitochondrial biogenesis, the insulin signalling pathway and adipogenesis (p < 0.01). These associations were replicated in an independent cohort. Bariatric surgery-induced weight loss led to reduced HMOX1 (0.024 ± 0.010 vs 0.010 ± 0.004 RU, p < 0.0001), whereas in rats, high-fat diet-induced weight gain resulted in increased Hmox1 mRNA levels (0.22 ± 0.15 vs 0.54 ± 0.22 RU, p = 0.005). These changes were in parallel with changes in BMI and adipose tissue markers of iron excess, adipogenesis and inflammation. In human adipocytes, iron excess and inflammation led to increased HMOX1 mRNA levels. HMOX1 induction (by haem arginate [hemin] administration), resulted in a significant reduction of mitochondrial respiratory capacity (including basal respiration and spare respiratory capacity), glucose uptake and adipogenesis in parallel with increased expression of inflammatory- and iron excess-related genes.
CONCLUSIONS/INTERPRETATION: HMOX1 is an important marker of iron excess-induced adipose tissue dysfunction and metabolic disturbances in human obesity.
目的/假设：已知脂肪组织中的铁过量会促进脂肪组织功能障碍。在此，我们旨在研究血红素加氧酶1（HMOX1）在铁过量诱导的脂肪组织功能障碍中可能发挥的作用。
采用横断面研究方法，在两个独立队列（n = 234和40）中分析皮下和内脏脂肪组织中HMOX1基因表达与肥胖的关系。我们还评估了体重减轻（n = 21）、体重增加（大鼠，n = 20）对HMOX1 mRNA的影响；人类脂肪细胞分化过程中HMOX1 mRNA水平；炎症和铁对脂肪细胞HMOX1的影响；以及HMOX1诱导的活性对脂肪细胞线粒体呼吸功能、葡萄糖摄取和脂肪生成的影响。
肥胖参与者的脂肪组织HMOX1增加（p = 0.01），且与肥胖相关的代谢紊乱、铁蓄积、炎症和氧化应激标志物呈正相关（p < 0.01）。HMOX1与线粒体生物发生、胰岛素信号通路和脂肪生成相关的mRNA呈负相关（p < 0.01）。这些关联在独立队列中得到重复验证。减肥手术导致HMOX1降低（0.024±0.010对0.010±0.004 RU，p < 0.0001），而在大鼠中，高脂饮食导致体重增加，Hmox1 mRNA水平升高（0.22±0.15对0.54±0.22 RU，p = 0.005）。这些变化与BMI以及脂肪组织中铁过量、脂肪生成和炎症标志物的变化平行。在人类脂肪细胞中，铁过量和炎症导致HMOX1 mRNA水平升高。HMOX1诱导（通过给予血红素精氨酸[氯高铁血红素]）导致线粒体呼吸能力（包括基础呼吸和备用呼吸能力）、葡萄糖摄取和脂肪生成显著降低，同时炎症和铁过量相关基因的表达增加。
结论/解读：HMOX1是铁过量诱导的人类肥胖脂肪组织功能障碍和代谢紊乱的重要标志物。
