LAPEC EA-4278, Avignon Université, 84000 Avignon, France.
C2VN, Aix-Marseille Université, INRA, INSERM, 13000 Marseille, France.
Microvasc Res. 2020 Jul;130:104003. doi: 10.1016/j.mvr.2020.104003. Epub 2020 Mar 19.
This study aimed to determine the effects of physical exercise on the angio-adaptive response in adipose tissue following weight loss in a mouse model of diet-induced obesity. We hypothesized that physical exercise stimulates angiogenesis through the regulation of Vascular endothelial growth factor-A (VEGF-A) pro-/Thrombospondin-1 (TSP-1) anti-angiogenic signal under the control of the Murine double-minute 2/Forkhead box Os (Mdm2/FoxOs) axis, as reported in skeletal muscle.
We studied the effects of 7 weeks-voluntary exercise (Ex) in C57Bl/6 control or diet-induced obese (HFS) mice on vascularization of white adipose tissue (AT).
Diet-induced obese sedentary (HFSsed) mice presented a powerful angiostatic control in all adipose tissues, under FoxOs protein regulation, leading to capillary rarefaction. Exercise increased expression of Mdm2, repressing the angiostatic control in favor of adipose vascular regrowth in normal chow (NCex) and HFSex mice. This phenomenon was associated with adipocytes microenvironment improvement, such as decreased adipocytes hypertrophy and adipose tissue inflammation. In addition, adipose angiogenesis stimulation by exercise through Mdm2 pro-angiogenic action, improved visceral adipose insulin sensitivity, activated browning process within subcutaneous adipose tissue (ScWAT) and decreased ectopic fat deposition (muscle, heart and liver) in obese HFSex mice. The overall result of this approach of therapy by physical exercise is an improvement of all systemic cardiometabolic parameters.
These data demonstrated the therapeutic efficacy of physical exercise against obesity-associated pathologies, and also offer new prospects for molecular therapies targeting the adipose angio-adaptation in obese humans.
本研究旨在确定在饮食诱导肥胖的小鼠模型中，减肥后身体活动对脂肪组织血管生成适应性反应的影响。我们假设身体活动通过调节血管内皮生长因子 A（VEGF-A）前/血小板反应蛋白-1（TSP-1）抗血管生成信号来刺激血管生成，正如在骨骼肌中报道的那样，受鼠双微体 2/Forkhead 盒 Os（Mdm2/FoxOs）轴的控制。
我们研究了 7 周的自愿运动（Ex）对 C57Bl/6 对照或饮食诱导肥胖（HFS）小鼠白色脂肪组织（AT）血管化的影响。
饮食诱导肥胖的久坐（HFSsed）小鼠在 FoxOs 蛋白调节下，所有脂肪组织均表现出强大的血管生成抑制作用，导致毛细血管稀疏。运动增加了 Mdm2 的表达，抑制了血管生成抑制作用，有利于正常饲料（NCex）和 HFSex 小鼠的脂肪血管再生。这种现象与脂肪细胞微环境的改善有关，例如脂肪细胞肥大和脂肪组织炎症的减少。此外，运动通过 Mdm2 的促血管生成作用刺激脂肪血管生成，改善了肥胖 HFSex 小鼠内脏脂肪的胰岛素敏感性，激活了皮下脂肪组织（ScWAT）中的棕色化过程，并减少了异位脂肪沉积（肌肉、心脏和肝脏）。这种身体运动治疗方法的总体结果是改善了所有系统的心脏代谢参数。
这些数据表明身体活动对肥胖相关疾病具有治疗效果，并为针对肥胖人群脂肪血管适应的分子治疗提供了新的前景。
