Börgeson Emma, Wallenius Ville, Syed Gulam H, Darshi Manjula, Lantero Rodriguez Juan, Biörserud Christina, Ragnmark Ek Malin, Björklund Per, Quiding-Järbrink Marianne, Fändriks Lars, Godson Catherine, Sharma Kumar
The Wallenberg Laboratory for Cardiovascular and Metabolic Research, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Bruna Stråket 16, S-413 45, Gothenburg, Sweden.
Centre for Renal Translational Medicine, Institute of Metabolomic Medicine, UC San Diego Health Sciences, San Diego VA HealthCare System, Stein Clinical Research Building, Room 406, mail code 0711, 9500 Gilman Drive, La Jolla, CA, 92093, USA.
Diabetologia. 2017 Apr;60(4):729-739. doi: 10.1007/s00125-017-4211-9. Epub 2017 Feb 10.
AIMS/HYPOTHESIS: In this study, we aimed to evaluate the therapeutic potential of 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR), an activator of AMP-activated protein kinase, for ameliorating high-fat diet (HFD)-induced pathophysiology in mice. We also aimed to determine whether the beneficial effects of AICAR were dependent on adiponectin. Furthermore, human adipose tissue was used to examine the effect of AICAR ex vivo.
Six-week-old male C57BL/6J wild-type and Adipoq mice were fed a standard-fat diet (10% fat) or an HFD (60% fat) for 12 weeks and given vehicle or AICAR (500 μg/g) three times/week from weeks 4-12. Diet-induced pathophysiology was examined in mice after 11 weeks by IPGTT and after 12 weeks by flow cytometry and western blotting. Human adipose tissue biopsies from obese (BMI 35-50 kg/m) individuals were incubated with vehicle or AICAR (1 mmol/l) for 6 h at 37°C, after which inflammation was characterised by ELISA (TNF-α) and flow cytometry.
AICAR attenuated adipose inflammation in mice fed an HFD, promoting an M1-to-M2 macrophage phenotype switch, while reducing infiltration of CD8 T cells. AICAR treatment of mice fed an HFD partially restored glucose tolerance and attenuated hepatic steatosis and kidney disease, as evidenced by reduced albuminuria (p < 0.05), urinary HO (p < 0.05) and renal superoxide levels (p < 0.01) in both wild-type and Adipoq mice. AICAR-mediated protection occurred independently of adiponectin, as similar protection was observed in wild-type and Adipoq mice. In addition, AICAR promoted an M1-to-M2 macrophage phenotype switch and reduced TNF-α production in tissue explants from obese human patients.
CONCLUSIONS/INTERPRETATION: AICAR may promote metabolic health and protect against obesity-induced systemic diseases in an adiponectin-independent manner. Furthermore, AICAR reduced inflammation in human adipose tissue explants, suggesting by proof-of-principle that the drug may reduce obesity-induced complications in humans.
ClinicalTrials.gov NCT02322073.
目的/假设：在本研究中，我们旨在评估5-氨基咪唑-4-甲酰胺核糖核苷酸（AICAR）（一种AMP激活的蛋白激酶激活剂）改善高脂饮食（HFD）诱导的小鼠病理生理的治疗潜力。我们还旨在确定AICAR的有益作用是否依赖于脂联素。此外，使用人体脂肪组织在体外研究AICAR的作用。
六周龄雄性C57BL/6J野生型和Adipoq基因敲除小鼠喂食标准脂肪饮食（10%脂肪）或高脂饮食（60%脂肪）12周，并在第4至12周每周三次给予溶剂或AICAR（500μg/g）。在第11周通过腹腔内葡萄糖耐量试验（IPGTT）以及在第12周通过流式细胞术和蛋白质免疫印迹法检测小鼠饮食诱导的病理生理。将肥胖（BMI 35 - 50kg/m²）个体的人体脂肪组织活检标本与溶剂或AICAR（1mmol/L）在37°C孵育6小时，之后通过酶联免疫吸附测定（ELISA）（肿瘤坏死因子-α（TNF-α））和流式细胞术对炎症进行表征。
AICAR减轻了高脂饮食喂养小鼠的脂肪炎症，促进了M1到M2巨噬细胞表型转换，同时减少了CD8 T细胞浸润。AICAR对高脂饮食喂养小鼠的治疗部分恢复了葡萄糖耐量，减轻了肝脂肪变性和肾病，野生型和Adipoq基因敲除小鼠的蛋白尿减少（p < 0.05）、尿8-羟基脱氧鸟苷（HO）减少（p < 0.05）以及肾超氧化物水平降低（p < 0.01）证明了这一点。AICAR介导的保护作用独立于脂联素发生，因为在野生型和Adipoq基因敲除小鼠中观察到了类似的保护作用。此外，AICAR促进了肥胖人类患者组织外植体中M1到M2巨噬细胞表型转换并减少了TNF-α产生。
结论/解读：AICAR可能以不依赖脂联素的方式促进代谢健康并预防肥胖诱导的全身性疾病。此外，AICAR减少了人体脂肪组织外植体中的炎症，原则性证明表明该药物可能减少人类肥胖诱导的并发症。
ClinicalTrials.gov NCT02322073
