CCAAT enhancer-binding protein (C͞EBP), C͞EBP␣, and peroxisome proliferator activated receptor (PPAR)␥ act in a cascade where C͞EBP activates expression of C͞EBP␣ and PPAR␥, which then function as pleiotropic activators of genes that produce the adipocyte phenotype. When growth-arrested 3T3-L1 preadipocytes are induced to differentiate, C͞EBP is rapidly expressed but still lacks DNA-binding activity. After a long (14-hour) lag, glycogen synthase kinase 3 enters the nucleus, which correlates with hyperphosphorylation of C͞EBP and acquisition of DNA-binding activity. Concurrently, 3T3-L1 preadipocytes synchronously enter S phase and undergo mitotic clonal expansion, a prerequisite for terminal differentiation. Ex vivo and in vitro experiments with C͞EBP show that phosphorylation of Thr-188 by mitogen-activating protein kinase ''primes'' C͞EBP for subsequent phosphorylation on Ser-184 and Thr-179 by glycogen synthase kinase 3, acquisition of DNA-binding function, and transactivation of the C͞EBP␣ and PPAR␥ genes. The delayed transactivation of the C͞EBP␣ and PPAR␥ genes by C͞EBP appears necessary to allow mitotic clonal expansion, which would otherwise be prevented, because C͞EBP␣ and PPAR␥ are antimitotic.3T3-L1 preadipocyte ͉ cell cycle ͉ differentiation ͉ mitotic clonal expansion C CAAT enhancer-binding protein  (C͞EBP) is expressed early in the adipocyte differentiation program, first initiating mitotic clonal expansion (MCE) (1, 2) and later activating expression of C͞EBP␣ and peroxisome proliferator-activated receptor ␥ (PPAR␥) (3-6), pleiotropic activators of adipocyte genes (3,4,7,8). Both MCE and expression of C͞EBP␣ and PPAR␥ are required for differentiation (1, 2, 9). When treated with differentiation inducers, growth-arrested 3T3-L1 preadipocytes synchronously reenter the cell cycle, undergo approximately two rounds of mitosis, then exit the cell cycle and enter the terminal stages of differentiation. Transcriptional activation of the C͞EBP␣ and PPAR␥ genes is induced by the interaction of C͞EBP with C͞EBP regulatory elements in these gene promoters (3-6).Although expression of C͞EBP occurs within 2 h of induction of differentiation, acquisition of DNA-binding activity and thus transcription of the C͞EBP␣ and PPAR␥ genes are delayed (10). Acquisition of DNA-binding activity begins after a long lag (Ϸ14 h), concurrent with the entry of S phase at the onset of MCE and transcription of the C͞EBP␣ and PPAR␥ genes (ref. 10 and Fig. 1). This lag appears necessary, because C͞EBP␣ and PPAR␥ are antimitotic (11-15), and their premature expression would otherwise prevent the MCE required for differentiation. To elucidate the mechanism by which C͞EBP acquires DNAbinding activity, we considered the possibility that covalent modification of C͞EBP occurs during this time window.Several lines of evidence indicated that C͞EBP can be phosphorylated in vitro by a variety of kinases, including PKA (16), PKC (16), mitogen-activated protein kinase (MAPK) (17), and Ca 2ϩ -calmodulin-dependent kinase II (18). ...
lysyl oxidase ͉ preadipocyte ͉ Smad4 ͉ adipogenesis ͉ differentiation
In humans, obesity is associated with long QT, increased frequency of premature ventricular complexes, and sudden cardiac death. The mechanisms of the pro-arrhythmic electrophysiologic remodeling of obesity are poorly understood. We tested the hypothesis that there is decreased expression of voltage-gated potassium channels in the obese heart, leading to long QT. Using implanted telemeters, we found that diet-induced obese (DIO) wild-type mice have impaired cardiac repolarization, demonstrated by long QT, as well as more frequent ventricular ectopy, similar to obese humans. DIO mice have reduced protein and mRNA levels of the potassium channel Kv1.5 caused by a reduction of the transcription factor cyclic AMP response element binding protein (CREB) in DIO hearts. We found that CREB knock-down by siRNA reduces Kv1.5, CREB binds to the Kv1.5 promoter in the heart, and CREB increases transcription of mouse and human Kv1.5 promoters. The reduction in CREB protein during lipotoxicity can be rescued by inhibiting protein kinase D (PKD). Our results identify a mechanism for obesity-induced electrophysiologic remodeling in the heart, namely PKD-induced reduction of CREB, which in turn decreases expression of the potassium channel Kv1.5.
Apply It! From this article, the reader should be able to • Identify top 20 fitness trends for Australia, Brazil, China, Europe, Mexico, Spain, and the United States. • Recognize individual and unique fitness trends represented within Australia, Brazil, China, Europe, Mexico, Spain, and the United States.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.