Department of Food Science and Nutrition, University of Minnesota, Twin Cities, MN, USA.
Institute for Genomic Engineered Animal Models of Human Diseases, Dalian Medical University, Dalian, China.
Mol Metab. 2019 Jun;24:18-29. doi: 10.1016/j.molmet.2019.03.007. Epub 2019 Mar 20.
Aging increases the risk for development of adipose tissue dysfunction, insulin resistance, dyslipidemia, and liver steatosis. Lipocalin 2 (Lcn2) deficient mice are more prone to diet-induced obesity and metabolic dysfunction, indicating a protective role for Lcn2 in younger mice. In this study, we determined whether overexpressing Lcn2 in adipose tissue can protect against age-related metabolic deterioration.
We developed ap2-promoter-driven Lcn2 transgenic (Tg) mice and aged Lcn2 Tg mice for the metabolic assessments.
We found decreased adipocyte size in inguinal white adipose tissue (iWAT) from 10-month-old Lcn2 Tg mice relative to WT. This was accompanied by increased markers of adipogenesis in iWAT and attenuation of the age-related decline in AMP-activated protein kinase (AMPK) phosphorylation in adipose tissue depots. In addition to improvements in adipose tissue function, whole-body metabolic homeostasis was maintained in aged Lcn2 Tg mice. This included improved glucose tolerance and reduced serum triglycerides in older Lcn2 Tg mice relative to WT mice. Further, liver morphology and liver lipid levels were improved in older Lcn2 Tg mice, alongside a decrease in markers of liver inflammation and fibrosis.
We demonstrate that overexpression of Lcn2 in adipose tissue not only preserves adipose tissue function during aging but also promotes maintenance of glucose tolerance, decreases dyslipidemia, and prevents liver lipid accumulation and steatosis.
衰老会增加脂肪组织功能障碍、胰岛素抵抗、血脂异常和肝脂肪变性的风险。脂联素 2（Lcn2）缺乏的小鼠更容易发生饮食诱导的肥胖和代谢功能障碍，这表明 Lcn2 在年轻小鼠中具有保护作用。在这项研究中，我们确定了脂肪组织中过表达 Lcn2 是否可以预防与年龄相关的代谢恶化。
我们开发了 ap2 启动子驱动的 Lcn2 转基因（Tg）小鼠，并对其进行了代谢评估。
我们发现 10 月龄的 Lcn2 Tg 小鼠腹股沟白色脂肪组织（iWAT）中的脂肪细胞体积减小，而与 WT 相比，iWAT 中的脂肪生成标志物增加，脂肪组织中 AMP 激活蛋白激酶（AMPK）磷酸化的年龄相关下降得到缓解。除了改善脂肪组织功能外，衰老的 Lcn2 Tg 小鼠还维持了全身代谢稳态。这包括改善葡萄糖耐量和降低老年 Lcn2 Tg 小鼠的血清甘油三酯水平，而 WT 小鼠则相反。此外，老年 Lcn2 Tg 小鼠的肝脏形态和肝脏脂质水平得到改善，同时肝脏炎症和纤维化的标志物减少。
我们证明，脂肪组织中 Lcn2 的过表达不仅可以在衰老过程中维持脂肪组织功能，还可以促进葡萄糖耐量的维持，降低血脂异常，并防止肝脏脂质积累和脂肪变性。
