Hypoglycemia and impaired hepatic glucose production in mice with a deletion of the C/EBPβ gene
Sha Liu, … , Richard W. Hanson, Jacob E. Friedman
Sha Liu, … , Richard W. Hanson, Jacob E. Friedman
Published January 15, 1999
Citation Information: J Clin Invest. 1999;103(2):207-213. https://doi.org/10.1172/JCI4243.
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Article

Hypoglycemia and impaired hepatic glucose production in mice with a deletion of the C/EBPβ gene

Abstract

The transcription factor CCAAT/enhancer-binding protein β (C/EBPβ) 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/EBPβ on glucose homeostasis, we studied mice with a targeted deletion of the gene for C/EBPβ–/– mice. Adult C/EBPβ–/– 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/EBPβ–/– mice. Unexpectedly, both the basal and glucagon-stimulated hepatic cyclic adenosine monophosphate (cAMP) levels were lower in C/EBPβ–/– mice, indicating an essential role for C/EBPβ 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/EBPβ–/– mice. FFA release from isolated adipose tissue in response to epinephrine was 68% lower in C/EBPβ–/– mice than in control animals; however, N6,O2′-dibutyryladenosine (Bt2) cAMP stimulated a twofold increase in FFA release in C/EBPβ–/– compared with no further increase in wild-type mice. Because a deletion in the gene for C/EBPβ 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/EBPβ activity.

Authors

Sha Liu, Colleen Croniger, Carmen Arizmendi, Mariko Harada-Shiba, Jianming Ren, Valeria Poli, Richard W. Hanson, Jacob E. Friedman

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Liver gene expression in adult WT mice and mice homozygous for a deletio...
Liver gene expression in adult WT mice and mice homozygous for a deletion of the C/EBPβ gene (–/–). (a) Ten-week-old female C/EBPβ–/– and WT mice were fasted overnight before being anesthetized and sacrificed, and the total liver RNA was isolated. The RNA was subjected to Northern blot analysis, and the blot was hybridized sequentially with probes for PEPCK, G6Pase, and glucokinase. Results were normalized to the level of actin mRNA and expressed relative to WT controls. (b) Effect of Bt2cAMP on the expression of genes for PEPCK, G6Pase, and glucokinase. Mice were fed a high-carbohydrate diet (81% sucrose) for 5 days, followed by intraperitoneal injection with 60 mg Bt2cAMP/kg of body weight and 25 μg of theophylline in 150 μl of saline, and were sacrificed 2 h later (27). The livers were frozen at –80°C until they were analyzed. RNA was isolated and Northern blot analysis carried out as described in a. The bars represent the mean ± SEM of four to six animals per group. PEPCK, phosphoenolpyruvate carboxykinase; G6Pase, glucose-6-phosphatase; Bt2, N6,O2′-dibutyryladenosine.