Department of Medicine Huddinge, Lipid laboratory, Karolinska Institutet, Novum, NVS D4, Hälsovägen 7, 14186, Stockholm, Sweden.
Diabetologia. 2015 Sep;58(9):2115-23. doi: 10.1007/s00125-015-3673-x. Epub 2015 Jun 27.
AIMS/HYPOTHESIS: Dysregulated expression of metabolic and inflammatory genes is a prominent consequence of obesity causing insulin resistance and type 2 diabetes. Finding causative factors is essential to understanding progression of these pathologies and discovering new therapeutic targets. The transcription factor V-maf musculoaponeurotic fibrosarcoma oncogene homologue B (MAFB) is highly expressed in human white adipose tissue (WAT). However, its role in the regulation of WAT function is elusive. We aimed to characterise MAFB expression and function in human WAT in the context of obesity and insulin resistance.
MAFB mRNA expression was evaluated in human WAT from seven cohorts with large inter-individual variation in BMI and metabolic features. Insulin-induced adipocyte lipogenesis and lipolysis were measured and correlated with MAFB expression. MAFB regulation during adipogenesis and the effects of MAFB suppression in human adipocytes was investigated. MAFB regulation by TNF-α was examined in human primary adipocytes and THP-1 monocytes/macrophages.
MAFB expression in human adipocytes is upregulated during adipogenesis, increases with BMI in WAT, correlates with adverse metabolic features and is decreased after weight loss. MAFB downregulation decreases proinflammatory gene expression in adipocytes and interferes with TNF-α effects. Interestingly, MAFB is differentially regulated by TNF-α in adipocytes (suppressed) and THP-1 cells (upregulated). Further, MAFB is primarily expressed in WAT macrophages/monocytes and its expression correlates with macrophage and inflammatory markers.
CONCLUSIONS/INTERPRETATION: Our findings indicate that MAFB is a regulator and a marker of adipose tissue inflammation, a process that subsequently causes insulin resistance.
目的/假设：代谢和炎症基因表达失调是肥胖导致胰岛素抵抗和 2 型糖尿病的一个突出后果。寻找致病因素对于理解这些病理的进展和发现新的治疗靶点至关重要。转录因子 V-maf 肌肉腱膜纤维肉瘤癌基因同系物 B（MAFB）在人体白色脂肪组织（WAT）中高度表达。然而，其在调节 WAT 功能中的作用尚不清楚。我们旨在研究肥胖和胰岛素抵抗背景下 MAFB 在人体 WAT 中的表达和功能。
在 7 个人群队列中，评估了 MAFB mRNA 表达与 BMI 和代谢特征的个体间差异。测量了胰岛素诱导的脂肪细胞脂肪生成和脂肪分解，并与 MAFB 表达相关联。研究了 MAFB 在脂肪生成过程中的调节作用以及 MAFB 抑制对人脂肪细胞的影响。研究了 TNF-α对人原代脂肪细胞和 THP-1 单核细胞/巨噬细胞中 MAFB 的调节作用。
人脂肪细胞中的 MAFB 表达在脂肪生成过程中上调，在 WAT 中随 BMI 增加而增加，与不良代谢特征相关，并在体重减轻后降低。MAFB 下调会降低脂肪细胞中的促炎基因表达并干扰 TNF-α的作用。有趣的是，MAFB 在脂肪细胞（受抑制）和 THP-1 细胞（上调）中由 TNF-α差异调节。此外，MAFB 主要在 WAT 巨噬细胞/单核细胞中表达，其表达与巨噬细胞和炎症标志物相关。
结论/解释：我们的研究结果表明，MAFB 是脂肪组织炎症的调节剂和标志物，这一过程随后导致胰岛素抵抗。
