CCAAT/enhancer-binding protein beta deletion reduces adiposity, hepatic steatosis, and diabetes in Lepr(db/db) mice.
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.
Schroeder-Gloeckler
Jill M
JM
Department of Pediatrics, University of Colorado at Denver and Health Sciences Center, Aurora, Colorado 80045, USA.
Rahman
Shaikh Mizanoor
SM
Janssen
Rachel C
RC
Qiao
Liping
L
Shao
Jianhua
J
Roper
Michael
M
Fischer
Stephanie J
SJ
Lowe
Erin
E
Orlicky
David J
DJ
McManaman
James L
JL
Palmer
Carol
C
Gitomer
William L
WL
Huang
Wan
W
O'Doherty
Robert M
RM
Becker
Thomas C
TC
Klemm
Dwight J
DJ
Jensen
Dalan R
DR
Pulawa
Leslie K
LK
Eckel
Robert H
RH
Friedman
Jacob E
JE
D050154:Adiposity / Q000187:drug effects / Q000235:genetics; D000818:Animals; D022782:CCAAT-Enhancer-Binding Protein-beta / Q000172:deficiency / Q000378:metabolism*; D002460:Cell Line; D003920:Diabetes Mellitus / Q000235:genetics / Q000378:metabolism* / Q000628:therapy; D004734:Energy Metabolism / Q000187:drug effects / Q000235:genetics; D005234:Fatty Liver / Q000235:genetics / Q000378:metabolism* / Q000628:therapy; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D007004:Hypoglycemic Agents / Q000494:pharmacology; D008687:Metformin / Q000494:pharmacology; D051379:Mice; D018345:Mice, Knockout; D009765:Obesity / Q000235:genetics / Q000378:metabolism* / Q000628:therapy; D047493:PPAR alpha / Q000096:biosynthesis; D047495:PPAR gamma / Q000096:biosynthesis; D010168:Palmitates / Q000494:pharmacology; D013230:Stearoyl-CoA Desaturase / Q000096:biosynthesis; D051780:Sterol Regulatory Element Binding Protein 1 / Q000096:biosynthesis; D014280:Triglycerides / Q000378:metabolism
D022782:CCAAT-Enhancer-Binding Protein-beta; D007004:Hypoglycemic Agents; D047493:PPAR alpha; D047495:PPAR gamma; D010168:Palmitates; C497388:Srebf1 protein, mouse; D051780:Sterol Regulatory Element Binding Protein 1; D014280:Triglycerides; D008687:Metformin; C490333:Scd1 protein, mouse; D013230:Stearoyl-CoA Desaturase