Peterson Richard G, Jackson Charles Van, Zimmerman Karen M, Alsina-Fernandez Jorge, Michael M Dodson, Emmerson Paul J, Coskun Tamer
Crown Bioscience - Indiana, Indianapolis, Indiana, United States of America.
Eli Lilly and Company, Indianapolis, Indiana, United States of America.
PLoS One. 2017 Jun 22;12(6):e0179856. doi: 10.1371/journal.pone.0179856. eCollection 2017.
The FATZO/Pco mouse is the result of a cross of the C57BL/6J and AKR/J strains. The crossing of these two strains and the selective inbreeding for obesity, insulin resistance and hyperglycemia has resulted in an inbred strain exhibiting obesity in the presumed presence of an intact leptin pathway. Routinely used rodent models for obesity and diabetes research have a monogenic defect in leptin signaling that initiates obesity. Given that obesity and its sequelae in humans are polygenic in nature and not associated with leptin signaling defects, the FATZO mouse may represent a more translatable rodent model for study of obesity and its associated metabolic disturbances. The FATZO mouse develops obesity spontaneously when fed a normal chow diet. Glucose intolerance with increased insulin levels are apparent in FATZO mice as young as 6 weeks of age. These progress to hyperglycemia/pre-diabetes and frank diabetes with decreasing insulin levels as they age. The disease in these mice is multi-faceted, similar to the metabolic syndrome apparent in obese individuals, and thus provides a long pre-diabetic state for determining the preventive value of new interventions. We have assessed the utility of this new model for the pre-clinical screening of agents to stop or slow progression of the metabolic syndrome to severe diabetes. Our assessment included: 1) characterization of the spontaneous development of disease, 2) comparison of metabolic disturbances of FATZO mice to control mice and 3) validation of the model with regard to the effectiveness of current and emerging anti-diabetic agents; rosiglitazone, metformin and semaglutide.
Male FATZO mice spontaneously develop significant metabolic disease when compared to normal controls while maintaining hyperglycemia in the presence of high leptin levels and hyperinsulinemia. The disease condition responds to commonly used antidiabetic agents.
FATZO/Pco小鼠是C57BL/6J和AKR/J品系杂交的产物。这两个品系的杂交以及对肥胖、胰岛素抵抗和高血糖的选择性近亲繁殖，产生了一个在假定瘦素途径完整的情况下表现出肥胖的近交系。常用于肥胖和糖尿病研究的啮齿动物模型在瘦素信号传导方面存在单基因缺陷，从而引发肥胖。鉴于人类肥胖及其后遗症本质上是多基因的，且与瘦素信号传导缺陷无关，FATZO小鼠可能是一种更具可转化性的啮齿动物模型，用于研究肥胖及其相关的代谢紊乱。FATZO小鼠在喂食正常饲料时会自发发生肥胖。早在6周龄时，FATZO小鼠就出现了葡萄糖不耐受且胰岛素水平升高的情况。随着年龄增长，这些情况会发展为高血糖/糖尿病前期和明显的糖尿病，同时胰岛素水平下降。这些小鼠的疾病具有多方面特点，类似于肥胖个体中明显的代谢综合征，因此为确定新干预措施的预防价值提供了一个较长的糖尿病前期状态。我们评估了这个新模型在临床前筛选阻止或减缓代谢综合征进展为严重糖尿病药物方面的效用。我们的评估包括：1）疾病自发发展的特征描述，2）FATZO小鼠与对照小鼠代谢紊乱的比较，3）用当前和新出现的抗糖尿病药物（罗格列酮、二甲双胍和司美格鲁肽）验证该模型。
与正常对照相比，雄性FATZO小鼠在高瘦素水平和高胰岛素血症的情况下维持高血糖，同时自发发生严重的代谢疾病。该疾病状态对常用的抗糖尿病药物有反应。
