CCAAT/Enhancer-binding protein β deletion reduces adiposity, hepatic steatosis, and diabetes in Leprdb/db mice

CCAAT/enhancer-binding protein beta (C/EBP beta) plays a key role in initiation of adipogenesis in adipose tissue and gluconeogenesis in liver; however, the role of C/ EBP beta in hepatic lipogenesis remains undefined. Here we show that C/EBP beta inactivation in Leprdb/ db mice attenuates obesity, fatty liver, and diabetes. In addition to impaired adipogenesis, livers from C/EB beta(-/-) x Lepr(db/db) mice had dramatically decreased triglyceride content and reduced lipogenic enzyme activity. C/EBP beta deletion in Lepr(db/db) mice down-regulated peroxisome proliferator-activated receptor gamma 2 (PPAR gamma 2) and stearoyl-CoA desaturase-1 and up-regulated PPAR alpha independent of SREBP1c. Conversely, C/EBP beta overexpression in wild-type mice increased PPAR gamma 2 and stearoyl-CoA desaturase-1 mRNA and hepatic triglyceride content. In FAO cells, overexpression of the liver inhibiting form of C/EBP beta or C/EBP beta RNA interference attenuated palmitate-induced triglyceride accumulation and reduced PPAR gamma 2 and triglyceride levels in the liver in vivo. Leptin and the anti-diabetic drug metformin acutely down-regulated C/EBP beta expression in hepatocytes, whereas fatty acids up-regulate C/EBP beta expression. These data provide novel evidence linking C/EBP beta expression to lipogenesis and energy balance with important implications for the treatment of obesity and fatty liver disease.