The Lundberg Laboratory for Diabetes Research, Department of Molecular and Clinical Medicine, the Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
Bioscience Metabolism, Research and Early Development, Cardiovascular, Renal and Metabolic (CVRM), BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden.
Mol Metab. 2020 Feb;32:15-26. doi: 10.1016/j.molmet.2019.11.016. Epub 2019 Dec 17.
Bone morphogenetic protein 4 (BMP4) adeno-associated viral vectors of serotype 8 (AAV8) gene therapy targeting the liver prevents the development of obesity in initially lean mice by browning the large subcutaneous white adipose tissue (WAT) and enhancing energy expenditure. Here, we examine whether this approach could also reduce established obesity.
Dietary-induced obese C57BL6/N mice received AAV8 BMP4 gene therapy at 17-18 weeks of age. They were kept on a high-fat diet and phenotypically characterized for an additional 10-12 weeks. Following termination, the mice underwent additional characterization in vitro.
Surprisingly, we observed no effect on body weight, browning of WAT, or energy expenditure in these obese mice, but whole-body insulin sensitivity and glucose tolerance were robustly improved. Insulin signaling and insulin-stimulated glucose uptake were increased in both adipose cells and skeletal muscle. BMP4 also decreased hepatic glucose production and reduced gluconeogenic enzymes in the liver, but not in the kidney, in addition to enhancing insulin action in the liver.
Our findings show that BMP4 prevents, but does not reverse, established obesity in adult mice, while it improves insulin sensitivity independent of weight reduction. The BMP antagonist Noggin was increased in WAT in obesity, which may account for the lack of browning.
针对肝脏的 8 型腺相关病毒（AAV8）载体骨形态发生蛋白 4（BMP4）基因治疗可使原本偏瘦的小鼠的大型皮下白色脂肪组织（WAT）褐变，并增强能量消耗，从而预防肥胖的发生。在此，我们研究了这种方法是否也可以减轻已形成的肥胖。
饮食诱导肥胖的 C57BL6/N 小鼠在 17-18 周龄时接受 AAV8 BMP4 基因治疗。它们继续接受高脂肪饮食，并在另外 10-12 周内进行表型特征分析。实验结束后，对这些肥胖小鼠进行了进一步的体外特征分析。
令人惊讶的是，我们观察到这些肥胖小鼠的体重、WAT 褐变或能量消耗均无变化，但全身胰岛素敏感性和葡萄糖耐量得到了显著改善。胰岛素信号和胰岛素刺激的葡萄糖摄取在脂肪细胞和骨骼肌中均增加。BMP4 还降低了肝脏的葡萄糖产生，并减少了肝脏中的糖异生酶，但在肾脏中没有减少，此外还增强了肝脏中的胰岛素作用。
我们的研究结果表明，BMP4 可预防但不能逆转成年肥胖小鼠的肥胖，同时它可改善胰岛素敏感性，而与体重减轻无关。肥胖时 WAT 中 BMP 拮抗剂 Noggin 增加，这可能是褐变缺失的原因。
