Metabolic response of mice to a postnatal ablation of CCAAT/enhancer-binding protein alpha.
Although CCAAT/enhancer-binding protein alpha (C/EBPalpha) is essential for initiating or sustaining several metabolic processes during the perinatal period, the consequences of total ablation of C/EBPalpha during postnatal development have not been investigated. We have created a conditional knock-out model in which the administration of poly(I:C) caused a virtually total deletion of c/ebpalpha (C/EBPalpha(Delta/-) mice) in the liver, spleen, white and brown adipose tissues, pancreas, lung, and kidney of the mice. C/EBPalpha itself was completely ablated in the liver by day 4 after the injection of poly(I:C). There was no noticeable change in phenotype during the first 15 days after the injection. The mice maintained a normal level of fasting blood glucose and responded to the diabetogenic action of streptozotocin. From day 16 onward, the mice developed hypophagia, exhibited severe weight loss, lost triglyceride in white but not brown adipose tissue, became hypoglycemic and hypoinsulinemic, depleted their hepatic glycogen, and developed fatty liver. They also exhibited lowered plasma levels of free fatty acid, triglyceride, and cholesterol, as well as marked changes in hepatic mRNA for C/EBPdelta, peroxisome proliferator-activated receptor alpha, sterol regulatory element-binding protein 1, hydroxymethylglutaryl-coenzyme A reductase, and apolipoproteins. Although basal levels of hepatic mRNA for the cytosolic isoform of phosphoenolpyruvate carboxykinase and glucose-6-phosphatase were reduced, transcription of the genes for these enzymes was inducible by dibutyryl cyclic AMP in C/EBPalpha(Delta/-) mice. The animals died about 1 month after the injection of poly(I:C). These findings demonstrate that C/EBPalpha is essential for the survival of animals during postnatal life and that its ablation leads to distinct biphasic change in metabolic processes.
Yang
Jianqi
J
Department of Biochemistry, Case Western Reserve University School of Medicine, Cleveland, Ohio 44106-4935, USA. jxy22@pop.cwru.edu
Croniger
Colleen M
CM
Lekstrom-Himes
Julie
J
Zhang
Pu
P
Fenyus
Maris
M
Tenen
Daniel G
DG
Darlington
Gretchen J
GJ
Hanson
Richard W
RW
D000273:Adipose Tissue / Q000378:metabolism; D000483:Alleles; D000818:Animals; D001053:Apolipoproteins / Q000737:chemistry; D001786:Blood Glucose / Q000378:metabolism; D015152:Blotting, Northern; D015139:Blotting, Southern; D015153:Blotting, Western; D001835:Body Weight; D022763:CCAAT-Enhancer-Binding Protein-alpha / Q000378:metabolism / Q000502:physiology*; D051743:CCAAT-Enhancer-Binding Protein-delta / Q000378:metabolism; D002784:Cholesterol / Q000378:metabolism; D003433:Crosses, Genetic; D000242:Cyclic AMP / Q000378:metabolism; D003600:Cytosol / Q000737:chemistry; D005234:Fatty Liver / Q000378:metabolism; D017353:Gene Deletion; D005838:Genotype; D005941:Glucokinase / Q000378:metabolism; D005947:Glucose / Q000378:metabolism; D005952:Glucose-6-Phosphatase / Q000737:chemistry; D019298:Glucose-6-Phosphate / Q000378:metabolism; D006003:Glycogen / Q000378:metabolism; D006903:Hydroxymethylglutaryl CoA Reductases / Q000378:metabolism; D007700:Kinetics; D008099:Liver / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008957:Models, Genetic; D020411:Oligonucleotide Array Sequence Analysis; D047493:PPAR alpha / Q000378:metabolism; D019764:Phosphoenolpyruvate Carboxykinase (ATP) / Q000737:chemistry; D011066:Poly C; D011069:Poly I; D016133:Polymerase Chain Reaction; D020033:Protein Isoforms; D012333:RNA, Messenger / Q000378:metabolism; D013311:Streptozocin / Q000494:pharmacology; D013997:Time Factors; D014018:Tissue Distribution; D014158:Transcription, Genetic; D014280:Triglycerides / Q000378:metabolism
D001053:Apolipoproteins; D001786:Blood Glucose; D022763:CCAAT-Enhancer-Binding Protein-alpha; D047493:PPAR alpha; D020033:Protein Isoforms; D012333:RNA, Messenger; D014280:Triglycerides; D051743:CCAAT-Enhancer-Binding Protein-delta; D011069:Poly I; D011066:Poly C; D019298:Glucose-6-Phosphate; D013311:Streptozocin; D006003:Glycogen; D002784:Cholesterol; D000242:Cyclic AMP; D006903:Hydroxymethylglutaryl CoA Reductases; D005941:Glucokinase; D005952:Glucose-6-Phosphatase; D019764:Phosphoenolpyruvate Carboxykinase (ATP); D005947:Glucose