Advanced Genomic Technology, LLC, Louisville, KY, USA.
Palo Alto Veterans Institute for Research, Palo Alto, CA, USA.
Sci Rep. 2019 Sep 25;9(1):13844. doi: 10.1038/s41598-019-50191-3.
Overweight children and adolescents are at high risk for adult and late life obesity. This report investigates some underlying mechanisms contributing to obesity during early life in an animal model. We generated a strain of transgenic mice, cU2, overexpressing human microRNA 34c, a microRNA functionally implicated in adipogenesis. Male and female cU2 mice exhibit significant weight gain, accompanied by marked increase in abdominal fat mass and metabolic abnormalities, including reduction of both glucose clearance rate and insulin sensitivity, as early as two months of age. Adipogenesis derailment at this early age is suggested by decreased expression of adiponectin, the fat mass and obesity-associated gene, and the adiponectin receptor R1, coupled with a reduction of the brown fat biomarker PAT2 and the adipogenesis inhibitor SIRT1. Notably, adiponectin is an important adipokine and an essential regulator of glucose and fatty acid homeostasis. cU2 mice may provide a crucial animal model for investigating the role of miR-34c in early onset insulin resistance and visceral fat mass increase, contributing to accelerated body weight gain and metabolic disorders. Intervention in this dysregulation may open a new preventive strategy to control early-life weight gain and abnormal insulin resistance, and thus prevalent adult and late life obesity.
超重的儿童和青少年成年后和晚年肥胖的风险很高。本报告研究了一种动物模型中导致生命早期肥胖的一些潜在机制。我们生成了一种过表达人源 microRNA 34c 的转基因小鼠品系 cU2，microRNA 34c 在脂肪生成中具有功能。雄性和雌性 cU2 小鼠表现出明显的体重增加，伴随着腹部脂肪量的显著增加和代谢异常，包括早在两个月大时葡萄糖清除率和胰岛素敏感性的降低。脂肪生成的这种早期脱轨是由脂联素、肥胖相关基因和脂联素受体 R1 的表达减少，以及棕色脂肪生物标志物 PAT2 和脂肪生成抑制剂 SIRT1 的减少所提示的。值得注意的是，脂联素是一种重要的脂肪因子，是葡萄糖和脂肪酸稳态的重要调节剂。cU2 小鼠可能为研究 miR-34c 在早期胰岛素抵抗和内脏脂肪量增加中的作用提供了一个重要的动物模型，导致体重加速增加和代谢紊乱。干预这种失调可能为控制生命早期体重增加和异常胰岛素抵抗提供一种新的预防策略，从而预防成年和晚年肥胖。
