C/EBP alpha is required for differentiation of white, but not brown, adipose tissue

The transcription factor CCAAT enhancer binding protein alpha (C/ EBP alpha ) is expressed at high levels in liver and adipose tissue. Cell culture stu dies show that C/EBP alpha is sufficient to trigger differentiation of prea dipocytes into mature adipocytes, suggesting a central role for C/EBP alpha in the development of adipose tissue. C/EBP alpha knockout mice die within 7-12 h after birth. Defective gluconeogenesis of the liver and subsequent hypoglycemia contribute to the early death of these animals. This short lif e span impairs investigation of the development of adipose tissue in these mice. To improve the survival of C/EBP alpha-/- animals, we generated a tra nsgenic line that expresses C/EBP alpha under the control of the albumin en hancer/promoter. This line was bred into the knockout strain to generate an imals that express C/EBPa in the liver but in no other tissue. The presence of the transgene improved survival of C/EBP alpha-/- animals almost 3-fold . Transgenic C/EBP alpha-/- animals at 7 days of age show an absence of s.c ., perirenal, and epididymal white fat despite excess lipid substrate in th e serum, whereas brown adipose tissue is somewhat hypertrophied and shows m inimal biochemical alterations. Interestingly, mammary gland fat tissue is present and exhibits normal morphology. The absence of white adipose tissue in many depots in the presence of high serum lipid levels shows that C/EBP alpha is required for the in vivo development of this tissue. In contrast, brown adipose tissue differentiation is independent of C/EBP alpha express ion. The presence of lipid in brown adipose tissue serves as an internal nu tritional control, indicating that neither nutritional intake nor lipoprote in composition is likely responsible for the absence of white fat.