TY - JOUR
T1 - CCAAT/enhancer-binding protein β deletion reduces adiposity, hepatic steatosis, and diabetes in Leprdb/db mice
AU - Schroeder-Gloeckler, Jill M.
AU - Rahman, Shaikh Mizanoor
AU - Janssen, Rachel C.
AU - Qiao, Liping
AU - Shao, Jianhua
AU - Roper, Michael
AU - Fischer, Stephanie J.
AU - Lowe, Erin
AU - Orlicky, David J.
AU - McManaman, James L.
AU - Palmer, Carol
AU - Gitomer, William L.
AU - Huang, Wan
AU - O'Doherty, Robert M.
AU - Becker, Thomas C.
AU - Klemm, Dwight J.
AU - Jensen, Dalan R.
AU - Pulawa, Leslie K.
AU - Eckel, Robert H.
AU - Friedman, Jacob E.
PY - 2007/5/25
Y1 - 2007/5/25
N2 - CCAAT/enhancer-binding protein β (C/EBPβ) plays a key role in initiation of adipogenesis in adipose tissue and gluconeogenesis in liver; however, the role of C/EBPβ in hepatic lipogenesis remains undefined. Here we show that C/EBPβ inactivation in Leprdb/db mice attenuates obesity, fatty liver, and diabetes. In addition to impaired adipogenesis, livers from C/EBPβ-/- x Leprdb/db mice had dramatically decreased triglyceride content and reduced lipogenic enzyme activity. C/EBPβ deletion in Leprdb/db mice down-regulated peroxisome proliferator-activated receptor γ2 (PPARγ2) and stearoyl-CoA desaturase-1 and up-regulated PPARα independent of SREBP1c. Conversely, C/EBPβ overexpression in wild-type mice increased PPARγ2 and stearoyl-CoA desaturase-1 mRNA and hepatic triglyceride content. In FAO cells, overexpression of the liver inhibiting form of C/EBPβ or C/EBPβ RNA interference attenuated palmitate-induced triglyceride accumulation and reduced PPARγ2 and triglyceride levels in the liver in vivo. Leptin and the anti-diabetic drug metformin acutely down-regulated C/EBPβ expression in hepatocytes, whereas fatty acids up-regulate C/EBPβ expression. These data provide novel evidence linking C/EBPβ expression to lipogenesis and energy balance with important implications for the treatment of obesity and fatty liver disease.
AB - CCAAT/enhancer-binding protein β (C/EBPβ) plays a key role in initiation of adipogenesis in adipose tissue and gluconeogenesis in liver; however, the role of C/EBPβ in hepatic lipogenesis remains undefined. Here we show that C/EBPβ inactivation in Leprdb/db mice attenuates obesity, fatty liver, and diabetes. In addition to impaired adipogenesis, livers from C/EBPβ-/- x Leprdb/db mice had dramatically decreased triglyceride content and reduced lipogenic enzyme activity. C/EBPβ deletion in Leprdb/db mice down-regulated peroxisome proliferator-activated receptor γ2 (PPARγ2) and stearoyl-CoA desaturase-1 and up-regulated PPARα independent of SREBP1c. Conversely, C/EBPβ overexpression in wild-type mice increased PPARγ2 and stearoyl-CoA desaturase-1 mRNA and hepatic triglyceride content. In FAO cells, overexpression of the liver inhibiting form of C/EBPβ or C/EBPβ RNA interference attenuated palmitate-induced triglyceride accumulation and reduced PPARγ2 and triglyceride levels in the liver in vivo. Leptin and the anti-diabetic drug metformin acutely down-regulated C/EBPβ expression in hepatocytes, whereas fatty acids up-regulate C/EBPβ expression. These data provide novel evidence linking C/EBPβ expression to lipogenesis and energy balance with important implications for the treatment of obesity and fatty liver disease.
UR - http://www.scopus.com/inward/record.url?scp=34447529373&partnerID=8YFLogxK
U2 - 10.1074/jbc.M701329200
DO - 10.1074/jbc.M701329200
M3 - Article
C2 - 17387171
AN - SCOPUS:34447529373
SN - 0021-9258
VL - 282
SP - 15717
EP - 15729
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
IS - 21
ER -