C/EBP beta, when expressed from the C/ebp alpha gene locus, can functionally replace C/EBP alpha in liver but not in adipose tissue

Knockout of C/EBP alpha causes a severe loss of liver function and, subsequ ently, neonatal lethality in mire. By using a gene replacement approach, we generated a new C/EBP alpha-null mouse strain in which C/EBP beta, in addi tion to its own expression, substituted for C/EBP alpha expression in tissu es. The homozygous mutant mice C/ebp alpha(beta/beta) are viable and fertil e and show none of the overt liver abnormalities found in the previous C/EB P alpha-null mouse line. Levels of hepatic PEPCK mRNA are not different bet ween C/ebp alpha(beta/beta) and wild-type mice. However, despite their norm al growth rate, C/ebp alpha(beta/beta) mice have markedly reduced fat stora ge in their white adipose tissue (WAT). Expression of two adipocyte-specifi c factors, adipsin and leptin, is significantly reduced in the WAT of C/ebp alpha(beta/beta) mice. In addition, expression of the non-adipocyte-specif ic genes for transferrin and cysteine dioxygenase is reduced in WAT but not in liver. Our study demonstrates that when expressed from the C/ebp alpha gene locus, C/EBP beta can act for C/EBP alpha to maintain liver functions during development. Moreover, our studies with the C/ebp alpha(beta/beta) m ice provide new insights into the nonredundant functions of C/EBP alpha and C/EBP beta on gene regulation in WAT.