Hypoglycemia and impaired hepatic glucose production in mice with a deletion of the C/EBPβ gene
Hypoglycemia and impaired hepatic glucose production in mice with a deletion of the C/EBPβ gene
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DOI：
10.1172/jci4243
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发表时间：
1999-01-01
影响因子：
15.9
通讯作者：
Friedman, JE
中科院分区：
文献类型：
--
作者：
Liu, S;Croniger, C;Friedman, JE
转录因子CCAAT/增强子结合蛋白β（C/EBP β）在肝脏和脂肪组织中富集，并控制编码重要代谢途径（包括脂肪生成和脂质合成）的多种基因的表达。为了研究C/EBP β对葡萄糖稳态的作用，我们研究了靶向缺失C/EBP β（-/-）基因的小鼠。成年C/EBP β（-/-）小鼠在禁食18小时后出现低血糖，伴有较低的肝葡萄糖生成（野生型小鼠的40%），血浆胰岛素无变化，血浆游离脂肪酸（FFA）浓度较低。胰腺钳夹期间胰高血糖素输注急性刺激野生型动物的肝脏葡萄糖产生38%，在C/EBP β（-/-）小鼠中未检测到变化。出乎意料的是，C/EBP β（-/-）小鼠的基础和胰高血糖素刺激的肝脏环磷酸腺苷（cAMP）水平均较低，表明C/EBP β在控制近端信号转导中起重要作用。空腹低血糖与磷酸烯醇式丙酮酸羧激酶（PEPCK）和葡萄糖-6-磷酸酶（G6 β）基因表达的正常水平相关，但在C/EBP β（-/-）小鼠中，净肝糖原分解受损。C/EBP beta（-/-）小鼠对肾上腺素的反应中，游离脂肪组织的FFA释放比对照组低68%;然而，N-6，O-2 '-二丁酰腺苷（Bt（2））cAMP刺激C/EBP beta（-/-）小鼠的FFA释放增加了两倍，而野生型小鼠则没有进一步增加。由于C/EBP β基因的缺失可降低血糖和循环FFA，基于设计降低C/EBP β活性的拮抗剂，它可能是治疗非胰岛素依赖型糖尿病和可能的肥胖症的重要治疗靶点。
The transcription factor CCAAT/enhancer-binding protein beta (C/EBP beta) is enriched in liver and adipose tissue and controls the expression of a wide variety of genes coding for important metabolic pathways, including gluconeogenesis and lipid synthesis. To investigate the role of C/EBP beta on glucose homeostasis, we studied mice with a targeted deletion of the gene for C/EBP beta(-/-) mice. Adult C/EBP beta(-/-) mice have hypoglycemia after an 18-hour fast, accompanied by lower hepatic glucose production (40% of that of wild-type mice), with no change in plasma insulin and a lower concentration of plasma free fatty acids (FFA). Glucagon infusion during a pancreatic clamp acutely stimulated hepatic glucose production by 38% in wild-type animals, with no change detected in C/EBP beta(-/-) mice. Unexpectedly, both the basal and glucagon-stimulated hepatic cyclic adenosine monophosphate (cAMP) levels were lower in C/EBP beta(-/-)mice, indicating an essential role for C/EBP beta in controlling proximal signal transduction. Fasting hypoglycemia was associated with normal levels of phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatase (G6Pase) gene expression, however net liver glycogenolysis was impaired in C/EBP beta(-/-)mice. FFA release from isolated adipose tissue in response to epinephrine was 68% lower in C/EBP beta(-/-)mice than in control animals; however, N-6,O-2'-dibutyryladenosine (Bt(2)) cAMP stimulated a twofold increase in FFA release in C/EBP beta(-/-) compared with no further increase in wild-type mice. Because a deletion in the gene for C/EBP beta reduces blood glucose and circulating FFA, it could be an important therapeutic target for the treatment of non-insulin-dependent diabetes and possibly obesity, based on designing antagonists that decrease C/EBP beta activity.