Mice with a deletion in the gene for CCAAT/enhancer-binding protein beta have an attenuated response to cAMP and impaired carbohydrate metabolism.
Fifty percent of the mice homozygous for a deletion in the gene for CCAAT/enhancer-binding protein beta (C/EBP beta-/- 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 beta-/- 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, beta-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 beta-/- 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 alpha and 27% increase in RII alpha in the particulate fraction of the livers of C/EBP beta-/- mice relative to wild type mice, with no change in the catalytic subunit (C alpha). Thus, a 45% increase in hepatic cAMP (relative to the wild type) would be required in C/EBP beta-/- mice to activate protein kinase A by 50%. In addition, the total activity of phosphodiesterase in the livers of C/EBP beta-/- 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 beta influences the regulation of carbohydrate metabolism by altering the level of hepatic cAMP and the activity of protein kinase A.
Croniger
C M
CM
Department of Biochemistry, Case Western Reserve University School of Medicine, Cleveland, Ohio 44106-4935, USA. cmc6@po.cwru.edu
Millward
C
C
Yang
J
J
Kawai
Y
Y
Arinze
I J
IJ
Liu
S
S
Harada-Shiba
M
M
Chakravarty
K
K
Friedman
J E
JE
Poli
V
V
Hanson
R W
RW
D020155:3-Hydroxybutyric Acid / Q000097:blood; D000262:Adenylyl Cyclases / Q000378:metabolism; D000641:Ammonia / Q000097:blood; D000818:Animals; D022782:CCAAT-Enhancer-Binding Protein-beta / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism*; D050260:Carbohydrate Metabolism; D000242:Cyclic AMP / Q000378:metabolism / Q000494:pharmacology*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D005508:Food Deprivation; D017353:Gene Deletion; D005934:Glucagon / Q000494:pharmacology; D005947:Glucose / Q000096:biosynthesis / Q000378:metabolism; D005952:Glucose-6-Phosphatase / Q000235:genetics; D007003:Hypoglycemia / Q000235:genetics; D008099:Liver / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D009584:Nitrogen / Q000097:blood; D010641:Phenotype; D019764:Phosphoenolpyruvate Carboxykinase (ATP) / Q000235:genetics; D010727:Phosphoric Diester Hydrolases / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D014508:Urea / Q000097:blood
D022782:CCAAT-Enhancer-Binding Protein-beta; D012333:RNA, Messenger; D000641:Ammonia; D014508:Urea; D005934:Glucagon; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D005952:Glucose-6-Phosphatase; D010727:Phosphoric Diester Hydrolases; D019764:Phosphoenolpyruvate Carboxykinase (ATP); D000262:Adenylyl Cyclases; D005947:Glucose; D009584:Nitrogen; D020155:3-Hydroxybutyric Acid