Abstract
CCAAT/enhancer-binding protein beta (C/EBPbeta) plays a key role in initiation of adipogenesis in adipose tissue and gluconeogenesis in liver; however, the role of C/EBPbeta in hepatic lipogenesis remains undefined. Here we show that C/EBPbeta inactivation in Lepr(db/db) mice attenuates obesity, fatty liver, and diabetes. In addition to impaired adipogenesis, livers from C/EBPbeta(-/-) x Lepr(db/db) mice had dramatically decreased triglyceride content and reduced lipogenic enzyme activity. C/EBPbeta deletion in Lepr(db/db) mice down-regulated peroxisome proliferator-activated receptor gamma2 (PPARgamma2) and stearoyl-CoA desaturase-1 and up-regulated PPARalpha independent of SREBP1c. Conversely, C/EBPbeta overexpression in wild-type mice increased PPARgamma2 and stearoyl-CoA desaturase-1 mRNA and hepatic triglyceride content. In FAO cells, overexpression of the liver inhibiting form of C/EBPbeta or C/EBPbeta RNA interference attenuated palmitate-induced triglyceride accumulation and reduced PPARgamma2 and triglyceride levels in the liver in vivo. Leptin and the anti-diabetic drug metformin acutely down-regulated C/EBPbeta expression in hepatocytes, whereas fatty acids up-regulate C/EBPbeta expression. These data provide novel evidence linking C/EBPbeta expression to lipogenesis and energy balance with important implications for the treatment of obesity and fatty liver disease.
Highlights
CCAAT/enhancer-binding protein  (C/EBP) plays a key role in initiation of adipogenesis in adipose tissue and gluconeogenesis in liver; the role of C/EBP in hepatic lipogenesis remains undefined
There was no difference in PPAR␥ in C/EBPϪ/Ϫ compared with WT mice; the levels of these data suggest that a significant portion of the effect of C/EBP deletion on reducing hepatic steatosis in C/EBPϪ/Ϫ x Leprdb/db may be mediated by inhibiting induction of lipogenic genes
Leptin and the AMPK Activator Metformin Reduce Hepatic C/EBP Expression—Because C/EBP deletion had a major effect on reducing the expression of lipogenic genes in Leprdb/db mice lacking the leptin receptor and in cells in response to lipid loading, we considered the possibility that C/EBP may be a target of leptin signaling
Summary
Animal Crossing and Genotyping The generation and genotyping procedures for C/EBPϪ/Ϫ and Leprdb/db mice have been described previously (26, 27). Mice deficient in C/EBP were backcrossed for up to eight generations with C57Bl/6J mice from The Jackson Laboratories (Bar Harbor, ME) and intercrosses between heterozygous mice derived from these littermates. Experiments and sample collection took place in the early afternoon after a 6-h daytime food withdrawal for steady state measurements. Plasma glucose levels were measured using an automatic glucose monitor (Roche Diagnostics). Serum insulin and adiponectin levels (Linco Research, St. Charles, MO and Alpco Diagnostics, Windham, NH), free fatty acids (Waco Diagnostics, Wako, TX), and TGs (Sigma-Aldrich) were measured using commercial kits, according to the manufacturers’ recommended protocols
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