Hypoglycemia and impaired hepatic glucose production in mice with a deletion of the C/EBPβ gene
Sha Liu, Colleen Croniger, Carmen Arizmendi, Mariko Harada-Shiba, Jianming Ren, Valeria Poli, Richard W. Hanson, Jacob E. Friedman
Sha Liu, Colleen Croniger, Carmen Arizmendi, Mariko Harada-Shiba, Jianming Ren, Valeria Poli, Richard W. Hanson, Jacob E. Friedman
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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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Impaired lipolysis in fat-pads from mice homozygous for a deletion of th...
Impaired lipolysis in fat-pads from mice homozygous for a deletion of the C/EBPβ gene (–/–). Periovarian fat-pads weighing 50–70 mg were isolated from fed C/EBPβ–/– and WT control mice and incubated in 1 ml of Krebs-Henseleit buffer with 3% porcine albumin and 5 mM glucose at 37°C in a shaking water bath (30 cycles/min) for 3 h. The medium was gassed with 95% O2/5% CO2. Of the two fat-pads from each animal, one was incubated with epinephrine (5 μg/ml) and 0.01% ascorbic acid, while the other was incubated with a maximal dose of Bt2cAMP (0.43 mg/ml) and theophylline (25 μg/ml). At the end of the 3-h incubation, the medium was frozen at –20°C for FFA and glycerol analysis as described in Methods. The DNA content was quantified in adipose tissue crude homogenates by a spectrofluorometric assay (31). The bars represent the mean ± SEM of 8–10 animals per group. *Significantly reduced compared with WT; P < 0.05. +Significantly increased compared with epinephrine-treated; P < 0.05. FFA, free fatty acids