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Identification of Creb3l4 as an essential negative regulator of adipogenesis

 T H Kim  ;  S H Jo  ;  H Choi  ;  J M Park  ;  M Y Kim  ;  H Nojima  ;  J W Kim  ;  Y H Ahn 
 CELL DEATH & DISEASE, Vol.5 : e1527, 2014 
Journal Title
Issue Date
3T3-L1 Cells ; Adipocytes/metabolism* ; Adipocytes/pathology ; Adipogenesis/genetics* ; Adiposity/genetics ; Animals ; CCAAT-Enhancer-Binding Proteins/genetics* ; CCAAT-Enhancer-Binding Proteins/metabolism ; Cell Differentiation ; Cyclic AMP Response Element-Binding Protein/genetics* ; Cyclic AMP Response Element-Binding Protein/metabolism ; GATA3 Transcription Factor/genetics ; GATA3 Transcription Factor/metabolism ; Gene Expression Regulation ; Glucose Tolerance Test ; Insulin Resistance ; Mice ; Mice, Knockout ; Obesity/genetics* ; Obesity/metabolism ; Obesity/pathology ; PPAR gamma/genetics* ; PPAR gamma/metabolism ; Signal Transduction
Understanding the molecular networks that regulate adipogenesis is crucial for combating obesity. However, the identity and molecular actions of negative regulators that regulate the early development of adipocytes remain poorly understood. In this study, we investigated the role of CREB3L4, a member of the CREB3-like family, in the regulation of adiposity. Constitutive overexpression of CREB3L4 resulted in the inhibition of adipocyte differentiation, whereas knockdown of Creb3l4 expression caused differentiation of preadipocytes into mature adipocytes, bypassing the mitotic clonal expansion step. In 3T3-L1 preadipocytes, Creb3l4 knockdown resulted in increased expression of peroxisome proliferator-activated receptor γ (PPARγ2) and CCAAT/enhancer binding protein (C/EBPα), either by increasing the protein stability of C/EBPβ or by decreasing the expression of GATA3, a negative regulator of PPARγ2 expression. Consequently, increased PPARγ2 and C/EBPα levels induced adipocyte differentiation, even in the presence of minimal hormonal inducer. Thus, it can be speculated that CREB3L4 has a role as gatekeeper, inhibiting adipogenesis in 3T3-L1 preadipocytes. Moreover, adipocytes of Creb3l4-knockout mice showed hyperplasia caused by increased adipogenesis, and exhibited improved glucose tolerance and insulin sensitivity, as compared with littermate wild-type mice. These results raise the possibility that Creb3l4 could be a useful therapeutic target in the fight against obesity and metabolic syndrome.
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1. College of Medicine (의과대학) > Dept. of Biochemistry and Molecular Biology (생화학-분자생물학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > BioMedical Science Institute (의생명과학부) > 1. Journal Papers
Yonsei Authors
Kim, Mi Young(김미영)
Kim, Jae Woo(김재우) ORCID logo https://orcid.org/0000-0001-5456-9495
Kim, Tae Hyun(김태현)
Ahn, Yong Ho(안용호) ORCID logo https://orcid.org/0000-0002-4133-0757
Jo, Seong Ho(조성호)
Choi, Hyeon Jin(최현진)
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