Background: Brown adipose tissue (BAT) has been regarded as a potential target organ to combat obesity and related metabolic disorders. However, the effect of BAT activation on the development of diabetic kidney disease (DKD) remains unclear.
Methods: Diabetic mice were induced by streptozotocin (STZ) combined with a high-fat diet. To activate BAT, mice were administered 1 mg/kg per day, i.p., CL316,243, a β3 -adrenergic receptor agonist, for 4 weeks. Blood glucose, serum lipids, adipokines, 24-hour urinary albumin, 8-hydroxydeoxyguanosine (8-OHdG), and circulating microRNA (miRNA) levels were analyzed, in addition to renal pathology. Histological changes (fibrosis, inflammation) were evaluated in the kidneys, as was the expression of oxidative stress-related genes. Renal signaling pathways (fibroblast growth factor [Fgf]21/β-klotho/FGF receptor 1c and AMP-activated protein kinase[AMPK]/sirtuin 1 [Sirt1]/peroxisome proliferator-activated receptor-γ coactivator-1α [Pgc1α]) were also evaluated.
Results: Compared with untreated STZ-diabetic mice, CL316,243 treatment reduced blood glucose, albeit not significantly (20.58 ± 3.55 vs 23.60 ± 3.90 mM), and significantly decreased triglycerides and low-density lipoprotein cholesterol and increased high-density lipoprotein cholesterol. Simultaneously, BAT activation significantly decreased 24-hour urinary albumin (34.21 ± 6.28 vs 70.46 ± 15.81 μg/24 h; P < 0.05) and 8-OHdG, improved renal fibrosis, inflammation, and oxidative stress, and ameliorated renal morphological abnormalities. In addition to enhancing BAT activity, CL316,243 significantly increased serum adiponectin concentrations and renal Fgf21 sensitivity, and reactivated the renal AMPK/Sirt1/Pgc1α signaling pathway. Furthermore, CL316,243 treatment increased levels of some circulating miRNAs and downregulated expression of their target genes in the kidney.
Conclusions: Activating BAT could improve kidney injury in diabetic mice via metabolic improvements and renal AMPK activation by beneficial adipokines and miRNAs.
背景: 棕色脂肪组织(brown adipose tissue, BAT)是潜在的防治肥胖及相关代谢紊乱的器官, 目前BAT激活对糖尿病肾脏病(diabetic kidney disease, DKD)的影响尚不清楚。 方法: 对链脲佐菌素(STZ)联合高脂饮食诱导的糖尿病小鼠, 连续4周每天给予1 mg/kg的β3-肾上腺素能受体激动剂CL316,243以激活BAT, 观察其对小鼠血糖、血脂、脂肪因子、24 h尿白蛋白、8-羟基脱氧鸟苷(8-OHdG)、循环microRNA分子(miRNA)水平、肾脏组织病理、肾脏纤维化、炎症及氧化应激的影响, 并对肾脏成纤维细胞生长因子Fgf 21/β-klotho/FGFR1c和AMPK/Sirt1/Pgc1α信号通路进行分析。 结果: CL316,243干预组的糖尿病小鼠的血糖水平呈降低趋势(20.58±3.55 vs. 23.60±3.90 mmol/L), 且甘油三酯和低密度脂蛋白胆固醇明显降低, 而高密度脂蛋白胆固醇明显升高。同时, BAT激活显著降低糖尿病小鼠的24 h尿白蛋白水平(34.21±6.28 vs. 70.46±15.81 μg/24 h；P<0.05)和8-OHdG水平, 明显改善肾脏纤维化、炎症和氧化应激, 并改善肾脏形态学异常。CL316,243干预不仅增强了糖尿病小鼠的BAT活性, 还显著提高了血清脂联素水平和肾脏Fgf 21敏感性, 激活了肾脏AMPK/Sirt1/Pgc1α信号通路。此外, CL316,243干预可显著增加某些循环miRNAs水平, 并下调相应的肾脏靶基因表达。 结论: BAT激活可显著改善糖尿病小鼠的代谢紊乱, 增加血中脂肪因子水平、上调循环中某些miRNAs表达、激活肾脏AMPK信号通路, 从而发挥对糖尿病小鼠的肾脏保护作用。.
Keywords: CL316,243; adipokine; brown adipose tissue; diabetic kidney disease; microRNA; 棕色脂肪组织; 糖尿病肾脏病; 脂肪因子.
© 2019 The Authors. Journal of Diabetes published by John Wiley & Sons Australia, Ltd and Ruijin Hospital, Shanghai Jiaotong University School of Medicine.