Impaired energy homeostasis in C/EBP alpha knockout mice

Mice homozygous for the targeted deletion of the c/ebp alpha gene, which expresses the CCAAT/enhancer-binding protein alpha (C/EBP alpha), did not store hepatic glycogen and died from hypoglycemia within 8 hours after birth. In these mutant mice, the amounts of glycogen synthase messenger RNA were 50 to 70 percent of normal and the transcriptional induction of the genes for two gluconeogenic enzymes, phosphoenolpyruvate carboxykinase and glucose-6-phosphatase, was delayed. The hepatocytes and adipocytes of the mutant mice failed to accumulate lipid and the expression of the gene for uncoupling protein, the defining marker of brown adipose tissue, was reduced. This study demonstrates that C/EBP alpha is critical for the establishment and maintenance of energy homeostasis in neonates.

[1]  A. Moorman,et al.  Relative roles of CCAAT/enhancer-binding protein beta and cAMP regulatory element-binding protein in controlling transcription of the gene for phosphoenolpyruvate carboxykinase (GTP). , 1993, The Journal of biological chemistry.

[2]  S. McKnight,et al.  The leucine zipper: a hypothetical structure common to a new class of DNA binding proteins. , 1988, Science.

[3]  J. Hawdon,et al.  The role of pancreatic insulin secretion in neonatal glucoregulation. II. Infants with disordered blood glucose homoeostasis. , 1993, Archives of disease in childhood.

[4]  R. Umek,et al.  CCAAT-enhancer binding protein: a component of a differentiation switch. , 1991, Science.

[5]  J. Liu,et al.  The role of the CCAAT/enhancer-binding protein in the transcriptional regulation of the gene for phosphoenolpyruvate carboxykinase (GTP) , 1990, Molecular and cellular biology.

[6]  H. Hers,et al.  Glycogen metabolism in the liver of the foetal rat. , 1974, The Biochemical journal.

[7]  Philippe Soriano,et al.  Loss of fumarylacetoacetate hydrolase is responsible for the neonatal hepatic dysfunction phenotype of lethal albino mice. , 1993, Genes & development.

[8]  K. Kaestner,et al.  Mouse insulin-responsive glucose transporter gene: characterization of the gene and trans-activation by the CCAAT/enhancer binding protein. , 1990, Proceedings of the National Academy of Sciences of the United States of America.

[9]  Mario R. Capecchi,et al.  Disruption of the proto-oncogene int-2 in mouse embryo-derived stem cells: a general strategy for targeting mutations to non-selectable genes , 1988, Nature.

[10]  R. Gitzelmann,et al.  Hepatic glycogen synthetase deficiency. Definition of syndrome from metabolic and enzyme studies on a 9-year-old girl. , 1977, Archives of disease in childhood.

[11]  F. Villarroya,et al.  CCAAT/enhancer binding proteins α and β are transcriptional activators of the brown fat uncoupling protein gene promoter , 1994 .

[12]  R. Erickson,et al.  Glucose-6-phosphatase deficiency caused by radiation-induced alleles at the albino locus in the mouse. , 1968, Proceedings of the National Academy of Sciences of the United States of America.

[13]  F. Bosch,et al.  Two genetically defined trans-acting loci coordinately regulate overlapping sets of liver-specific genes , 1990, Cell.

[14]  J. Ntambi,et al.  Differentiation-induced gene expression in 3T3-L1 preadipocytes: CCAAT/enhancer binding protein interacts with and activates the promoters of two adipocyte-specific genes. , 1989, Genes & development.

[15]  F. Ballard,et al.  The development of gluconeogenesis in rat liver: experiments in vivo. , 1969, The Biochemical journal.

[16]  S. McKnight,et al.  CCAAT/enhancer binding protein activates the promoter of the serum albumin gene in cultured hepatoma cells. , 1989, Genes & development.

[17]  J. Gordon,et al.  Tissue-specific expression, developmental regulation, and genetic mapping of the gene encoding CCAAT/enhancer binding protein. , 1989, Genes & development.

[18]  J. Himms-Hagen,et al.  Brown adipose tissue thermogenesis: interdisciplinary studies , 1990, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[19]  J. Świerczyński,et al.  Developmental changes of lipogenic enzyme activities and lipogenesis in brown adipose tissue and liver of the rat. , 1992, Comparative biochemistry and physiology. B, Comparative biochemistry.

[20]  R. Jaenisch,et al.  Is CCAAT/enhancer-binding protein a central regulator of energy metabolism? , 1989, Genes & development.

[21]  D. Ron,et al.  CHOP, a novel developmentally regulated nuclear protein that dimerizes with transcription factors C/EBP and LAP and functions as a dominant-negative inhibitor of gene transcription. , 1992, Genes & development.

[22]  W. Roesler,et al.  The liver-enriched transcription factor D-site-binding protein activates the promoter of the phosphoenolpyruvate carboxykinase gene in hepatoma cells. , 1992, The Journal of biological chemistry.

[23]  U. Schibler,et al.  DBP, a liver-enriched transcriptional activator, is expressed late in ontogeny and its tissue specificity is determined posttranscriptionally , 1990, Cell.

[24]  Allan Bradley,et al.  Targeted disruption of the c-src proto-oncogene leads to osteopetrosis in mice , 1991, Cell.