Metabolic Syndrome Group - BIOPROMET, Madrid Institute for Advanced Studies - IMDEA Food, CEI UAM+CSIC, Madrid, Spain.
Aging (Albany NY). 2020 Jun 25;12(12):11337-11348. doi: 10.18632/aging.103607.
Senescent cells accumulate with obesity in the white adipose tissue of mice and humans. These senescent cells enhance the pro-inflammatory environment that, with time, contributes to the onset of glucose intolerance and type 2 diabetes. Glucose intolerance in mouse models of obesity has been successfully reversed by the elimination of senescent cells with the senolytic compounds navitoclax or the combination of dasatinib and quercetin (D/Q). In this work, we generated obese mice by high-fat diet feeding, and treated them with five consecutive cycles of navitoclax or D/Q during 16 weeks. We observed an efficient reduction in the white adipose tissue of the senescence markers senescence-associated β-galactosidase activity, and at the end of the 5 cycles. Mice treated with both navitoclax and D/Q showed an improvement of their insulin sensitivity and glucose tolerance during a short period of time (cycles 3 and 4), that disappeared at the fifth cycle. Also, these mice tended to increase the expression at their adipose tissue of the adipogenic genes and, , as well as their plasma adiponectin levels. Together, our work shows that two different senolytic treatments, acting through independent pathways, are transiently effective in the treatment of obesity-induced metabolic disorders.
衰老细胞在肥胖小鼠和人类的白色脂肪组织中积累。这些衰老细胞增强了促炎环境，随着时间的推移，导致葡萄糖耐量受损和 2 型糖尿病的发生。用衰老细胞清除剂 navitoclax 或 dasatinib 和槲皮素 (D/Q) 的组合成功逆转了肥胖小鼠模型中的葡萄糖耐量受损。在这项工作中，我们通过高脂肪饮食喂养产生肥胖小鼠，并在 16 周内用五个连续周期的 navitoclax 或 D/Q 进行治疗。我们观察到在 5 个周期结束时，衰老标志物衰老相关β-半乳糖苷酶活性和的白色脂肪组织中的有效减少。用 navitoclax 和 D/Q 治疗的小鼠在短时间内（第 3 和第 4 周期）表现出胰岛素敏感性和葡萄糖耐量的改善，但在第 5 周期时消失。此外，这些小鼠倾向于增加其脂肪组织中脂肪生成基因和的表达，以及其血浆脂联素水平。总之，我们的工作表明，两种不同的衰老细胞清除剂通过独立途径作用，在治疗肥胖引起的代谢紊乱方面具有短暂的疗效。
