Activating transcription factor 4 regulates adipocyte differentiation via altering the coordinate expression of CCATT/enhancer binding protein β and peroxisome proliferator‐activated receptor γ

Adipose tissue is crucial for energy homeostasis and is a topic interest with respect to investigating the regulation of adipose tissue formation for the ever‐increasing health concerns of obesity and type 2 diabetes. Adipocyte differentiation is tightly regulated by the characteristic sequential expression change of adipocyte genes, including members of the CCATT/enhancer binding protein (C/EBP) family of transcription factors, peroxisome proliferator‐activated receptor γ and tribbles homolog 3. In the present study, we demonstrate that C/EBPβ and peroxisome proliferator‐activated receptor γ (but not tribbles homolog 3) are targeted for activation by activating transcription factor 4 (ATF4), a member of cAMP response element‐binding/activator transcription factor family. Importantly, overexpression of ATF4 in 3T3‐L1 cells enhanced adipogenesis, whereas small‐interfering ATF4 blocked conversion of preadipocytes to adipocytes. These findings were accomplished by altering the coordinate expression of adipogenic transcription factors. Taken together, our results suggest that ATF4 is a positive regulator of adipocyte differentiation. This notion is also supported by the results of the present study showing that the expression of ATF4 is induced during adipocyte differentiation. Thus, ATF4 could be an important regulator of energy homeostasis.

[1]  R. Friedline,et al.  GRP78 plays an essential role in adipogenesis and postnatal growth in mice , 2013, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[2]  R. Kaufman,et al.  ER stress signalling through eIF2α and CHOP, but not IRE1α, attenuates adipogenesis in mice , 2013, Diabetologia.

[3]  J. Seong,et al.  ATF3 inhibits adipocyte differentiation of 3T3-L1 cells. , 2012, Biochemical and biophysical research communications.

[4]  S. O’Rahilly,et al.  Investigating the involvement of the ATF6α pathway of the unfolded protein response in adipogenesis , 2011, International Journal of Obesity.

[5]  Q. Tang,et al.  Transcriptional activation of histone H4 by C/EBPβ during the mitotic clonal expansion of 3T3-L1 adipocyte differentiation , 2011, Molecular biology of the cell.

[6]  M. Melchiorre,et al.  Role of UBC9 in the regulation of the adipogenic program in 3T3-L1 adipocytes. , 2010, Endocrinology.

[7]  D. Galson,et al.  Activating transcription factor 4 regulates osteoclast differentiation in mice. , 2010, The Journal of clinical investigation.

[8]  Ursula A White,et al.  Transcriptional factors that promote formation of white adipose tissue , 2010, Molecular and Cellular Endocrinology.

[9]  B. Spiegelman,et al.  Transcriptional Control of Preadipocyte Determination by Zfp423 , 2010, Nature.

[10]  Ying Du,et al.  ATF4 regulates lipid metabolism and thermogenesis , 2010, Cell Research.

[11]  Arya M. Sharma,et al.  The chemical chaperone 4-phenylbutyrate inhibits adipogenesis by modulating the unfolded protein response[S] , 2009, Journal of Lipid Research.

[12]  S. Ishii,et al.  The Role of ATF-2 Family Transcription Factors in Adipocyte Differentiation: Antiobesity Effects of p38 Inhibitors , 2009, Molecular and Cellular Biology.

[13]  J. Graff,et al.  Atf4 Regulates Obesity, Glucose Homeostasis, and Energy Expenditure , 2009, Diabetes.

[14]  Xinmin Zhang,et al.  The IRE1alpha-XBP1 pathway of the unfolded protein response is required for adipogenesis. , 2009, Cell metabolism.

[15]  Jonathan Schug,et al.  PPARgamma and C/EBP factors orchestrate adipocyte biology via adjacent binding on a genome-wide scale. , 2008, Genes & development.

[16]  J. Friedman,et al.  Transcriptional regulation of adipogenesis by KLF4. , 2008, Cell metabolism.

[17]  I. Romao,et al.  Genetic and environmental interactions in obesity and type 2 diabetes. , 2008, Journal of the American Dietetic Association.

[18]  H. Hayashi,et al.  TRB3 suppresses adipocyte differentiation by negatively regulating PPARgamma transcriptional activity. , 2008, Journal of lipid research.

[19]  Margaret F. Gregor,et al.  Thematic review series: Adipocyte Biology. Adipocyte stress: the endoplasmic reticulum and metabolic disease Published, JLR Papers in Press, May 9, 2007. , 2007, Journal of Lipid Research.

[20]  C. Kahn,et al.  TRB3 Blocks Adipocyte Differentiation through the Inhibition of C/EBPβ Transcriptional Activity , 2007, Molecular and Cellular Biology.

[21]  Margaret F. Gregor,et al.  Adipocyte stress: the endoplasmic reticulum and metabolic disease , 2007 .

[22]  D. Klemm,et al.  Depletion of cAMP-response Element-binding Protein/ATF1 Inhibits Adipogenic Conversion of 3T3-L1 Cells Ectopically Expressing CCAAT/Enhancer-binding Protein (C/EBP) α, C/EBP β, or PPARγ2* , 2006, Journal of Biological Chemistry.

[23]  J. Auwerx,et al.  Oncogenic steroid receptor coactivator-3 is a key regulator of the white adipogenic program , 2006, Proceedings of the National Academy of Sciences.

[24]  D. Klemm,et al.  Depletion of cAMP-response element-binding protein/ATF1 inhibits adipogenic conversion of 3T3-L1 cells ectopically expressing CCAAT/enhancer-binding protein (C/EBP) alpha, C/EBP beta, or PPAR gamma 2. , 2006, The Journal of biological chemistry.

[25]  H. Hayashi,et al.  TRB3, a novel ER stress‐inducible gene, is induced via ATF4–CHOP pathway and is involved in cell death , 2005, The EMBO journal.

[26]  S. Akira,et al.  Krüppel-like transcription factor KLF5 is a key regulator of adipocyte differentiation. , 2005, Cell metabolism.

[27]  P. Sassone-Corsi,et al.  ATF4 Is a Substrate of RSK2 and an Essential Regulator of Osteoblast Biology Implication for Coffin-Lowry Syndrome , 2004, Cell.

[28]  C. Vinson,et al.  Role of CREB in Transcriptional Regulation of CCAAT/Enhancer-binding Protein β Gene during Adipogenesis* , 2004, Journal of Biological Chemistry.

[29]  C. Vinson,et al.  Dominant-negative C/EBP disrupts mitotic clonal expansion and differentiation of 3T3-L1 preadipocytes , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[30]  R. Paules,et al.  An integrated stress response regulates amino acid metabolism and resistance to oxidative stress. , 2003, Molecular cell.

[31]  M. Lane,et al.  CCAAT/enhancer-binding protein β is required for mitotic clonal expansion during adipogenesis , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[32]  Bruce M. Spiegelman,et al.  Obesity and the Regulation of Energy Balance , 2001, Cell.

[33]  R. Morrison,et al.  Hormonal signaling and transcriptional control of adipocyte differentiation. , 2000, The Journal of nutrition.

[34]  M. Reitman,et al.  Lipoatrophy Revisited , 2000, Trends in Endocrinology & Metabolism.

[35]  P. Puigserver,et al.  Transcriptional regulation of adipogenesis. , 2000, Genes & development.

[36]  J. Reusch,et al.  CREB Activation Induces Adipogenesis in 3T3-L1 Cells , 2000, Molecular and Cellular Biology.

[37]  G. Colditz,et al.  The disease burden associated with overweight and obesity. , 1999, JAMA.

[38]  B. Spiegelman,et al.  PPARγ Is Required for the Differentiation of Adipose Tissue In Vivo and In Vitro , 1999 .

[39]  K. Chien,et al.  PPARγ Is Required for Placental, Cardiac, and Adipose Tissue Development , 1999 .

[40]  S. Akira,et al.  Targeted disruption of ATF4 discloses its essential role in the formation of eye lens fibres , 1998, Genes to cells : devoted to molecular & cellular mechanisms.

[41]  S. Akira,et al.  Defective adipocyte differentiation in mice lacking the C/EBPβ and/or C/EBPδ gene , 1997 .

[42]  M. Manns,et al.  Copyright © 1997, American Society for Microbiology CREB Controls LAP/C/EBP � Transcription , 1997 .

[43]  S. McKnight,et al.  Cascade regulation of terminal adipocyte differentiation by three members of the C/EBP family of leucine zipper proteins. , 1995, Genes & development.

[44]  R. Umek,et al.  Regulated expression of three C/EBP isoforms during adipose conversion of 3T3-L1 cells. , 1991, Genes & development.