Inhibitory effect of a proline-to-alanine substitution at codon 12 of peroxisome proliferator-activated receptor-gamma 2 on thiazolidinedione-induced adipogenesis.

Peroxisome proliferator-activated receptor-gamma (PPARgamma) is a member of the nuclear hormone receptor superfamily of transcription factors and appears to be a key regulator of adipogenesis. Members of the thiazolidinedione class of insulin-sensitizing agents act as high-affinity ligands for PPARgamma, indicating that PPARgamma is also important in systemic insulin action. To determine whether Pro(12) --> Ala (P12A) mutation in PPARgamma gene contributes to the development of obesity or insulin sensitivity, we examined the effects of the P12A mutation on the function of PPARgamma by expression of the mutant protein in COS or 3T3-L1 cells. The abilities of the P12A mutant of PPARgamma to mediate both transcriptional activation of a luciferase reporter gene construct containing the peroxisome proliferator response element and adipogenesis induced by a thiazolidinedione drug were reduced compared with those of the wild-type protein. These results suggest that the P12A substitution in PPARgamma gene may be associated with abnormalities of adipose tissue formation and insulin sensitivity.

[1]  M. Kasuga,et al.  Inhibition of adipogenesis by a COOH-terminally truncated mutant of PPARgamma2 in 3T3-L1 cells. , 1999, Biochemical and biophysical research communications.

[2]  Satoshi Tanaka,et al.  PPARγ Mediates High-Fat Diet–Induced Adipocyte Hypertrophy and Insulin Resistance , 1999 .

[3]  V. Colantuoni,et al.  Pro12Ala substitution in the peroxisome proliferator-activated receptor-gamma2 is not associated with type 2 diabetes. , 1999, Diabetes.

[4]  O. Pedersen,et al.  Homozygosity of the Pro12Ala variant of the peroxisome proliferation-activated receptor-γ2 (PPAR-γ2): divergent modulating effects on body mass index in obese and lean Caucasian men , 1999, Diabetologia.

[5]  H. Häring,et al.  The PPARγ2 amino acid polymorphism Pro 12 Ala is prevalent in offspring of Type II diabetic patients and is associated to increased insulin sensitivity in a subgroup of obese subjects , 1999, Diabetologia.

[6]  S. Engeli,et al.  Pro12Ala missense mutation of the peroxisome proliferator activated receptor gamma and diabetes mellitus. , 1999, Biochemical and biophysical research communications.

[7]  C. Yen,et al.  Association of the Pro12Ala variant in the peroxisome proliferator-activated receptor-gamma2 gene with obesity in two Caucasian populations. , 1998, Diabetes.

[8]  Johan Auwerx,et al.  A Pro12Ala substitution in PPARγ2 associated with decreased receptor activity, lower body mass index and improved insulin sensitivity , 1998, Nature Genetics.

[9]  Y. Yazaki,et al.  Effect of the Pro12Ala variant of the human peroxisome proliferator-activated receptor gamma 2 gene on adiposity, fat distribution, and insulin sensitivity in Japanese men. , 1998, Biochemical and biophysical research communications.

[10]  A. Pfeiffer,et al.  Obesity associated with a mutation in a genetic regulator of adipocyte differentiation. , 1998, The New England journal of medicine.

[11]  G. Gyapay,et al.  Human peroxisome proliferator-activated receptor-gamma2: genetic mapping, identification of a variant in the coding sequence, and exclusion as the gene responsible for lipoatrophic diabetes. , 1998, Diabetes.

[12]  J. Auwerx,et al.  A genetic polymorphism of the peroxisome proliferator-activated receptor gamma gene influences plasma leptin levels in obese humans. , 1998, Human molecular genetics.

[13]  K. Silver,et al.  Molecular Scanning of the Human Peroxisome Proliferator Activated Receptor γ (hPPARγ) Gene in Diabetic Caucasians: Identification of a Pro12Ala PPARγ2 Missense Mutation , 1997 .

[14]  L. Hamann,et al.  Sensitization of diabetic and obese mice to insulin by retinoid X receptor agonists , 1997, Nature.

[15]  J. Lehmann,et al.  The structure - Activity relationship between peroxisome proliferator-activated receptor γ agonism and the antihyperglycemic activity of thiazolidinediones , 1996 .

[16]  S. Sugano,et al.  Efficient gene activation in mammalian cells by using recombinant adenovirus expressing site-specific Cre recombinase. , 1995, Nucleic acids research.

[17]  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.

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

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

[20]  K. Umesono,et al.  Convergence of 9-cis retinoic acid and peroxisome proliferator signalling pathways through heterodimer formation of their receptors , 1992, Nature.

[21]  J. Olefsky,et al.  Metabolic Effects of New Oral Hypoglycemic Agent CS-045 in NIDDM Subjects , 1992, Diabetes Care.

[22]  Yamamura Ken-ichi,et al.  Efficient selection for high-expression transfectants with a novel eukaryotic vector , 1991 .

[23]  Y. Iwamoto,et al.  Effect of New Oral Antidiabetic Agent CS-045 on Glucose Tolerance and Insulin Secretion in Patients with NIDDM , 1991, Diabetes Care.

[24]  K. Arai,et al.  SR alpha promoter: an efficient and versatile mammalian cDNA expression system composed of the simian virus 40 early promoter and the R-U5 segment of human T-cell leukemia virus type 1 long terminal repeat , 1988, Molecular and cellular biology.