Inhibition of Adipogenesis Through MAP Kinase-Mediated Phosphorylation of PPARγ

Adipocyte differentiation is an important component of obesity and other metabolic diseases. This process is strongly inhibited by many mitogens and oncogenes. Several growth factors that inhibit fat cell differentiation caused mitogen-activated protein (MAP) kinase-mediated phosphorylation of the dominant adipogenic transcription factor peroxisome proliferator-activated receptor γ (PPARγ) and reduction of its transcriptional activity. Expression of PPARγ with a nonphosphorylatable mutation at this site (serine-112) yielded cells with increased sensitivity to ligand-induced adipogenesis and resistance to inhibition of differentiation by mitogens. These results indicate that covalent modification of PPARγ by serum and growth factors is a major regulator of the balance between cell growth and differentiation in the adipose cell lineage.

[1]  C. Marshall,et al.  Activation of MAP kinase kinase is necessary and sufficient for PC12 differentiation and for transformation of NIH 3T3 cells , 1994, Cell.

[2]  H. Hauner.  Complete adipose differentiation of 3T3 L1 cells in a chemically defined medium: comparison to serum-containing culture conditions. , 1990, Endocrinology.

[3]  J. Larrick,et al.  Modulation of adipocyte differentiation by tumor necrosis factor and transforming growth factor beta , 1989, The Journal of cell biology.

[4]  B. Spiegelman,et al.  Regulation of adipocyte gene expression and differentiation by peroxisome proliferator activated receptor gamma. , 1995, Current opinion in genetics & development.

[5]  Z. Wu,et al.  Conditional ectopic expression of C/EBP beta in NIH-3T3 cells induces PPAR gamma and stimulates adipogenesis. , 1995, Genes & development.

[6]  R. Davis,et al.  Identification of substrate recognition determinants for human ERK1 and ERK2 protein kinases. , 1991, The Journal of biological chemistry.

[7]  B. Spiegelman,et al.  Differential activation of adipogenesis by multiple PPAR isoforms. , 1996, Genes & development.

[8]  P. Grimaldi,et al.  Cellular and molecular aspects of adipose tissue development. , 1992, Annual review of nutrition.

[9]  Y. Yazaki,et al.  Enhanced insulin-induced mitogenesis and mitogen-activated protein kinase activities in mutant insulin receptors with substitution of two COOH-terminal tyrosine autophosphorylation sites by phenylalanine. , 1992, The Journal of biological chemistry.

[10]  Myles Brown,et al.  Polarity-specific activities of retinoic acid receptors determined by a co-repressor , 1995, Nature.

[11]  B. Spiegelman,et al.  mPPAR gamma 2: tissue-specific regulator of an adipocyte enhancer. , 1994, Genes & development.

[12]  S. Freytag,et al.  Ectopic expression of the CCAAT/enhancer-binding protein alpha promotes the adipogenic program in a variety of mouse fibroblastic cells. , 1994, Genes & development.

[13]  Thorsten Heinzel,et al.  A CBP Integrator Complex Mediates Transcriptional Activation and AP-1 Inhibition by Nuclear Receptors , 1996, Cell.

[14]  M. Rodbell.  METABOLISM OF ISOLATED FAT CELLS. I. EFFECTS OF HORMONES ON GLUCOSE METABOLISM AND LIPOLYSIS. , 1964, The Journal of biological chemistry.

[15]  I. Goldfine,et al.  The metabolic and mitogenic effects of both insulin and insulin-like growth factor are enhanced by transfection of insulin receptors into NIH3T3 fibroblasts. , 1989, The Journal of biological chemistry.

[16]  H. Land,et al.  Advanced mammalian gene transfer: high titre retroviral vectors with multiple drug selection markers and a complementary helper-free packaging cell line. , 1990, Nucleic acids research.

[17]  D. Fraker,et al.  Characterization of differentiation factor/leukaemia inhibitory factor effect on lipoprotein lipase activity and mRNA in 3T3-L1 adipocytes. , 1994, Cytokine.

[18]  J. Lehmann,et al.  An Antidiabetic Thiazolidinedione Is a High Affinity Ligand for Peroxisome Proliferator-activated Receptor γ (PPARγ) (*) , 1995, The Journal of Biological Chemistry.

[19]  M. Lane,et al.  CCAAT/enhancer binding protein alpha is sufficient to initiate the 3T3-L1 adipocyte differentiation program. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[20]  O. MacDougald,et al.  Transcriptional regulation of gene expression during adipocyte differentiation. , 1995, Annual review of biochemistry.

[21]  B. Spiegelman,et al.  Stimulation of adipogenesis in fibroblasts by PPARγ2, a lipid-activated transcription factor , 1994, Cell.

[22]  Z. Wu,et al.  Induction of peroxisome proliferator-activated receptor gamma during the conversion of 3T3 fibroblasts into adipocytes is mediated by C/EBPbeta, C/EBPdelta, and glucocorticoids , 1996, Molecular and cellular biology.

[23]  H. Hauner,et al.  Effects of epidermal growth factor (EGF), platelet‐derived growth factor (PDGF) and fibroblast growth factor (FGF) on human adipocyte development and function , 1995, European journal of clinical investigation.

[24]  J. Lawrence,et al.  Signal transduction and protein phosphorylation in the regulation of cellular metabolism by insulin. , 1992, Annual review of physiology.

[25]  G. Serrero.  EGF inhibits the differentiation of adipocyte precursors in primary cultures. , 1987, Biochemical and biophysical research communications.

[26]  B. Spiegelman,et al.  Regulation of PPAR gamma gene expression by nutrition and obesity in rodents. , 1996, The Journal of clinical investigation.

[27]  D. Picard,et al.  Activation of the unliganded estrogen receptor by EGF involves the MAP kinase pathway and direct phosphorylation. , 1996, The EMBO journal.

[28]  B. O’Malley,et al.  Sequence and Characterization of a Coactivator for the Steroid Hormone Receptor Superfamily , 1995, Science.

[29]  R. Treisman,et al.  Regulation of transcription by MAP kinase cascades. , 1996, Current opinion in cell biology.

[30]  G. Ringold,et al.  Differential effects of fibroblast growth factor and tumor promoters on the initiation and maintenance of adipocyte differentiation , 1989, The Journal of cell biology.

[31]  Daniel Metzger,et al.  Activation of the Estrogen Receptor Through Phosphorylation by Mitogen-Activated Protein Kinase , 1995, Science.

[32]  D. Ron,et al.  Tumor necrosis factor-induced reversal of adipocytic phenotype of 3T3-L1 cells is preceded by a loss of nuclear CCAAT/enhancer binding protein (C/EBP). , 1992, The Journal of clinical investigation.

[33]  G. Serrero,et al.  Physiological role of epidermal growth factor on adipose tissue development in vivo. , 1991, Proceedings of the National Academy of Sciences of the United States of America.

[34]  H. Sul,et al.  Control of adipocyte differentiation. , 1995, The Biochemical journal.

[35]  J. Sambrook,et al.  Molecular Cloning: A Laboratory Manual , 2001 .

[36]  B. Spiegelman,et al.  Adipogenesis and Obesity: Rounding Out the Big Picture , 1996, Cell.

[37]  G. Löffler,et al.  Adipose conversion of 3T3-L1 cells in a serum-free culture system depends on epidermal growth factor, insulin-like growth factor I, corticosterone, and cyclic AMP. , 1990, The Journal of biological chemistry.

[38]  B. Spiegelman,et al.  Transdifferentiation of myoblasts by the adipogenic transcription factors PPAR gamma and C/EBP alpha. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[39]  P. Smith,et al.  Insulin-like growth factor-I is an essential regulator of the differentiation of 3T3-L1 adipocytes. , 1988, The Journal of biological chemistry.

[40]  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.