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J. Biol. Chem., Vol. 276, Issue 1, 629-638, January 5, 2001
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From the Departments of Biochemistry and Nutrition, Case Western
Reserve University School of Medicine, Cleveland, Ohio 44106-4935, the § Department of Biochemistry, Meharry Medical College,
Nashville, Tennessee 37208, and the Fifty percent of the mice homozygous
for a deletion in the gene for CCAAT/enhancer-binding protein
Mice with a Deletion in the Gene for CCAAT/Enhancer-binding
Protein
Have an Attenuated Response to cAMP and Impaired
Carbohydrate Metabolism*
,
, and Department of Molecular
Biology, University of Dundee,
Dundee, DD1 4HN Scotland, United Kingdom
(C/EBP
/ mice; B phenotype) die within 1 to 2 h after birth
of hypoglycemia. They do not mobilize their hepatic glycogen or induce
the cytosolic form of phosphoenolpyruvate carboxykinase (PEPCK).
Administration of cAMP resulted in mobilization of glycogen, induction
of PEPCK mRNA, and a normal blood glucose; these mice survived beyond
2 h postpartum. Adult C/EBP/ mice (A phenotype) also had
difficulty in maintaining blood glucose levels during starvation.
Fasting these mice for 16 or 30 h resulted in lower levels of
hepatic PEPCK mRNA, blood glucose, -hydroxybutyrate, blood urea
nitrogen, and gluconeogenesis when compared with control mice. The
concentration of hepatic cAMP in these mice was 50% of controls, but
injection of theophylline, together with glucagon, resulted in a normal
cAMP levels. Agonists (glucagon, epinephrine, and isoproterenol) and
other effectors of activation of adenylyl cyclase were the same in
liver membranes isolated from C/EBP/ mice and littermates. The
hepatic activity of cAMP-dependent protein kinase was 80%
of wild type mice. There was a 79% increase in the concentration of
RI
and 27% increase in RII in the particulate fraction of the
livers of C/EBP/ mice relative to wild type mice, with no change
in the catalytic subunit (C). Thus, a 45% increase in hepatic cAMP
(relative to the wild type) would be required in C/EBP/ mice to
activate protein kinase A by 50%. In addition, the total activity of
phosphodiesterase in the livers of C/EBP/ mice, as well as the
concentration of mRNA for phosphodiesterase 3A (PDE3A) and PDE3B
was approximately 25% higher than in control animals, suggesting
accelerated degradation of cAMP. C/EBP influences the regulation of
carbohydrate metabolism by altering the level of hepatic cAMP and the
activity of protein kinase A.
*
This research was supported in part by National Institutes
of Health Grants DK-25541 (to R. W. H.) and DK-50272 (to J. E. F.)
and National Science Foundation Grant MCB 9905070 (to I. J. A.).The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
Supported by National Institutes of Health Metabolism Training
Program, DK-07319. To whom correspondence should be addressed: Dept. of
Biochemistry, Case Western Reserve University School of Medicine,
Cleveland, Ohio 44106-4935. Tel.: 216-368-5302; Fax: 216-368-4544;
E-mail: cmc6@po.cwru.edu.
Copyright © 2001 by The American Society for Biochemistry and Molecular Biology, Inc.
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