Elevated GH/IGF-I, Due to Somatotrope-Specific Loss of Both IGF-I and Insulin Receptors, Alters Glucose Homeostasis and Insulin Sensitivity in a Diet-Dependent Manner
Elevated GH/IGF-I, Due to Somatotrope-Specific Loss of Both IGF-I and Insulin Receptors, Alters Glucose Homeostasis and Insulin Sensitivity in a Diet-Dependent Manner
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DOI：
10.1210/en.2011-1447
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发表时间：
2011-12-01
期刊：
影响因子：
4.8
通讯作者：
Kineman, Rhonda D.
中科院分区：
文献类型：
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作者：
Gahete, Manuel D.;Cordoba-Chacon, Jose;Kineman, Rhonda D.
由于生长激素特异性Cre介导的IGF-I受体(IgfIr)和胰岛素受体(Insr)基因(IgfIr、Insr)失活，内源性GH(2-3倍)和IGF-I(1.2-1.4倍)升高，建立了一种独特的小鼠模型。我们证明HIGH小鼠的代谢表型是饮食依赖的，不同于其他小鼠模型中观察到的GH过量，这是由于异位异源转基因表达或垂体肿瘤形成所致。内源性GH升高会促进瘦体重和全身脂肪氧化，但对肥胖的影响很小，即使是对饮食诱导的肥胖的反应也是如此。当热量摄入减少时，尽管胰岛素敏感性低/正常，但高GH可改善葡萄糖清除，这可能部分是由于IGF-I和胰岛素输出增加所致。然而，当热量摄入过多时，GH升高会促进肝脏脂肪堆积、胰岛素抵抗、高血糖和酮症。高水平的小鼠模型是研究内源性循环生长激素水平在调节健康和疾病中所起作用的有用工具。(内分泌学152：4825-4837,2011)
A unique mouse model was developed with elevated endogenous GH (2- to 3-fold) and IGF-I (1.2- to 1.4-fold), due to somatotrope-specific Cre-mediated inactivation of IGF-I receptor (IgfIr) and insulin receptor (Insr) genes (IgfIr, Insr(rGHpCre), referred to as HiGH mice). We demonstrate that the metabolic phenotype of HiGH mice is diet dependent and differs from that observed in other mouse models of GH excess due to ectopic heterologous transgene expression or pituitary tumor formation. Elevated endogenous GH promotes lean mass and whole-body lipid oxidation but has minimal effects on adiposity, even in response to diet-induced obesity. When caloric intake is moderated, elevated GH improves glucose clearance, despite low/normal insulin sensitivity, which may be explained in part by enhanced IGF-I and insulin output. However, when caloric intake is in excess, elevated GH promotes hepatic lipid accumulation, insulin resistance, hyperglycemia, and ketosis. The HiGH mouse model represents a useful tool to study the role endogenous circulating GH levels play in regulating health and disease. (Endocrinology 152: 4825-4837, 2011)