PPARγ and Diabetes: Beyond the Genome and Towards Personalized Medicine

Abstract

Purpose of Review

Full and partial synthetic agonists targeting the transcription factor PPARγ are contained in FDA-approved insulin-sensitizing drugs and used for the treatment of metabolic syndrome-related dysfunctions. Here, we discuss the association between PPARG genetic variants and drug efficacy, as well as the role of alternative splicing and post-translational modifications as contributors to the complexity of PPARγ signaling and to the effects of synthetic PPARγ ligands.

Recent Findings

PPARγ regulates the transcription of several target genes governing adipocyte differentiation and glucose and lipid metabolism, as well as insulin sensitivity and inflammatory pathways. These pleiotropic functions confer great relevance to PPARγ in physiological regulation of whole-body metabolism, as well as in the etiology of metabolic disorders. Accordingly, PPARG gene mutations, nucleotide variations, and post-translational modifications have been associated with adipose tissue disorders and the related risk of insulin resistance and type 2 diabetes (T2D). Moreover, PPARγ alternative splicing isoforms—generating dominant-negative isoforms mainly expressed in human adipose tissue—have been related to impaired PPARγ activity and adipose tissue dysfunctions. Thus, multiple regulatory levels that contribute to PPARγ signaling complexity may account for the beneficial as well as adverse effects of PPARγ agonists. Further targeted analyses, taking into account all these aspects, are needed for better deciphering the role of PPARγ in human pathophysiology, especially in insulin resistance and T2D.

Summary

The therapeutic potential of full and partial PPARγ synthetic agonists underlines the clinical significance of this nuclear receptor. PPARG mutations, polymorphisms, alternative splicing isoforms, and post-translational modifications may contribute to the pathogenesis of metabolic disorders, also influencing the responsiveness of pharmacological therapy. Therefore, in the context of the current evidence-based trend to personalized diabetes management, we highlight the need to decipher the intricate regulation of PPARγ signaling to pave the way to tailored therapies in patients with insulin resistance and T2D.

This is a preview of subscription content, access via your institution.

Fig. 1
Fig. 2

References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. 1.

    Boitier E, Gautier JC, Roberts R. Advances in understanding the regulation of apoptosis and mitosis by peroxisome-proliferator activated receptors in pre-clinical models: relevance for human health and disease. Comp Hepatol. 2003;2:3.

    PubMed  PubMed Central  Google Scholar 

  2. 2.

    Berger J, Moller DE. The mechanisms of action of PPARs. Annu Rev Med. 2002;53:409–35.

    CAS  PubMed  Google Scholar 

  3. 3.

    Monsalve FA, Pyarasani RD, Delgado-Lopez F, Moore-Carrasco R. Peroxisome proliferator-activated receptor targets for the treatment of metabolic diseases. Mediators Inflamm. 2013;2013:549627.

    PubMed  PubMed Central  Google Scholar 

  4. 4.

    Guerriero G. Vertebrate sex steroid receptors: evolution, ligands, and neurodistribution. Ann N Y Acad Sci. 2009;1163:154–68.

    CAS  PubMed  Google Scholar 

  5. 5.

    Chandra V, Huang P, Hamuro Y, Raghuram S, Wang Y, Burris TP, et al. Structure of the intact PPAR-gamma-RXR- nuclear receptor complex on DNA. Nature. 2008;456:350–6.

    PubMed  PubMed Central  Google Scholar 

  6. 6.

    Hummasti S, Tontonoz P. The peroxisome proliferator-activated receptor N-terminal domain controls isotype-selective gene expression and adipogenesis. Mol Endocrinol. 2006;20:1261–75.

    CAS  PubMed  Google Scholar 

  7. 7.

    Rastinejad F. Retinoid X receptor and its partners in the nuclear receptor family. Curr Opin Struct Biol. 2001;11:33–8.

    CAS  PubMed  Google Scholar 

  8. 8.

    Miyata KS, McCaw SE, Marcus SL, Rachubinski RA, Capone JP. The peroxisome proliferator-activated receptor interacts with the retinoid X receptor in vivo. Gene. 1994;148:327–30.

    CAS  PubMed  Google Scholar 

  9. 9.

    Lefterova MI, Haakonsson AK, Lazar MA, Mandrup S. PPARγamma and the global map of adipogenesis and beyond. Trends Endocrinol Metabol. TEM. 2014;25:293–302.

    CAS  Google Scholar 

  10. 10.

    Ogawa S, Lozach J, Jepsen K, Sawka-Verhelle D, Perissi V, Sasik R, et al. A nuclear receptor corepressor transcriptional checkpoint controlling activator protein 1-dependent gene networks required for macrophage activation. Proc Natl Acad Sci U S A. 2004;101:14461–6.

    CAS  PubMed  PubMed Central  Google Scholar 

  11. 11.

    Mangelsdorf DJ, Evans RM. The RXR heterodimers and orphan receptors. Cell. 1995;83:841–50.

    CAS  PubMed  Google Scholar 

  12. 12.

    Ricci CG, Silveira RL, Rivalta I, Batista VS, Skaf MS. Allosteric pathways in the PPARγ-RXRα nuclear receptor complex. Sci Rep. 2016;6:19940.

    CAS  PubMed  PubMed Central  Google Scholar 

  13. 13.

    Kojetin DJ, Matta-Camacho E, Hughes TS, Srinivasan S, Nwachukwu JC, Cavett V, et al. Structural mechanism for signal transduction in RXR nuclear receptor heterodimers. Nat Commun. 2015;6:8013.

    CAS  PubMed  PubMed Central  Google Scholar 

  14. 14.

    Tontonoz P, Spiegelman BM. Fat and beyond: the diverse biology of PPARgamma. Annu Rev Biochem. 2008;77:289–312.

    CAS  PubMed  Google Scholar 

  15. 15.

    Zoete V, Grosdidier A, Michielin O. Peroxisome proliferator-activated receptor structures: ligand specificity, molecular switch and interactions with regulators. Biochim Biophys Acta. 1771;2007:915–25.

    Google Scholar 

  16. 16.

    McKenna NJ, O’Malley BW. Combinatorial control of gene expression by nuclear receptors and coregulators. Cell. 2002;108:465–74.

    CAS  PubMed  Google Scholar 

  17. 17.

    Ahmadian M, Suh JM, Hah N, Liddle C, Atkins AR, Downes M, et al. PPARγ signaling and metabolism: the good, the bad and the future. Nat Med. 2013;19:557–66.

    CAS  PubMed  Google Scholar 

  18. 18.

    Farmer SR. Transcriptional control of adipocyte formation. Cell Metab. 2006;4:263–73.

    CAS  PubMed  PubMed Central  Google Scholar 

  19. 19.

    Rosen ED, MacDougald OA. Adipocyte differentiation from the inside out. Nat Rev Mol Cell Biol. 2006;7:885–96.

    CAS  PubMed  Google Scholar 

  20. 20.

    Lehrke M, Lazar MA. The many faces of PPARgamma. Cell. 2005;123:993–9.

    CAS  PubMed  Google Scholar 

  21. 21.

    Pascual G, Fong AL, Ogawa S, Gamliel A, Li AC, Perissi V, et al. A SUMOylation-dependent pathway mediates transrepression of inflammatory response genes by PPAR-gamma. Nature. 2005;437:759–63.

    CAS  PubMed  PubMed Central  Google Scholar 

  22. 22.

    Lemberger T, Desvergne B, Wahli W. Peroxisome proliferator-activated receptors: a nuclear receptor signaling pathway in lipid physiology. Annu Rev Cell Dev Biol. 1996;12:335–63.

    CAS  PubMed  Google Scholar 

  23. 23.

    Tang QQ, Lane MD. Adipogenesis: from stem cell to adipocyte. Annu Rev Biochem. 2012;81:715–36.

    CAS  PubMed  Google Scholar 

  24. 24.

    Imai T, Takakuwa R, Marchand S, Dentz E, Bornert JM, Messaddeq N, et al. Peroxisome proliferator-activated receptor gamma is required in mature white and brown adipocytes for their survival in the mouse. Proc Natl Acad Sci U S A. 2004;101:4543–7.

    CAS  PubMed  PubMed Central  Google Scholar 

  25. 25.

    Tontonoz P, Hu E, Spiegelman BM. Stimulation of adipogenesis in fibroblasts by PPAR gamma 2, a lipid-activated transcription factor. Cell. 1994;79:1147–56 Erratum in: Cell 1995;80:following 957.

    CAS  PubMed  Google Scholar 

  26. 26.

    Katafuchi T, Holland WL, Kollipara RK, Kittler R, Mangelsdorf DJ, Kliewer SA. PPARγ-K107 SUMOylation regulates insulin sensitivity but not adiposity in mice. Proc Natl Acad Sci U S A. 2018;115:12102–11.

    CAS  PubMed  PubMed Central  Google Scholar 

  27. 27.

    Kraakman MJ, Liu Q, Postigo-Fernandez J, Ji R, Kon N, Larrea D, et al. PPARγ deacetylation dissociates thiazolidinedione’s metabolic benefits from its adverse effects. J Clin Invest. 2018;128:2600–12.

    PubMed  PubMed Central  Google Scholar 

  28. 28.

    Broekema MF, Savage DB, Monajemi H, Kalkhoven E. Gene-gene and gene-environment interactions in lipodystrophy: lessons learned from natural PPARγ mutants. Biochim Biophys Acta Mol Cell Biol Lipids. 1864;2019:715–32.

    Google Scholar 

  29. 29.

    Floyd ZE, Stephens JM. Controlling a master switch of adipocyte development and insulin sensitivity: covalent modifications of PPARγ. Biochim Biophys Acta. 1822;2012:1090–5.

    Google Scholar 

  30. 30.

    Choi JH, Banks AS, Estall JL, Kajimura S, Boström P, Laznik D, et al. Anti-diabetic drugs inhibit obesity-linked phosphorylation of PPARgamma by Cdk5. Nature. 2010;466:451–6.

    CAS  PubMed  PubMed Central  Google Scholar 

  31. 31.

    Fang T, Di Y, Li G, Cui X, Shen N, Li Y, et al. Effects of telmisartan on TNFα induced PPARγ phosphorylation and insulin resistance in adipocytes. Biochem Biophys Res Commun. 2018;503:3044–9.

    CAS  PubMed  Google Scholar 

  32. 32.

    Ribeiro Filho HV, Bernardi Videira N, Bridi AV, et al. Screening for PPAR non-Agonist ligands followed by characterization of a hit, AM-879, with additional no-adipogenic and cdk5-mediated phosphorylation inhibition properties. Front Endocrinol (Lausanne). 2018;9:11.

    Google Scholar 

  33. 33.

    Pan DS, Wang W, Liu NS, et al. Chiglitazar preferentially regulates gene expression via configuration-restricted binding and phosphorylation inhibition of PPARγ. PPAR Res. 2017;2017:4313561.

    PubMed  PubMed Central  Google Scholar 

  34. 34.

    Xie X, Zhou X, Chen W, et al. L312, a novel PPARγ ligand with potent anti-diabetic activity by selective regulation. Biochim Biophys Acta. 2015;1850:62–72.

    CAS  PubMed  Google Scholar 

  35. 35.

    Kolli V, Stechschulte LA, Dowling AR, Rahman S, Czernik PJ, Lecka-Czernik B. Partial agonist, telmisartan, maintains PPARγ serine 112 phosphorylation, and does not affect osteoblast differentiation and bone mass. PLoS One. 2014;9:e96323.

    PubMed  PubMed Central  Google Scholar 

  36. 36.

    Lehmann JM, Moore LB, Smith-Oliver TA, Wilkison WO, Willson TM, Kliewer SA. An antidiabetic thiazolidinedione is a high affinity ligand for peroxisome proliferator-activated receptor gamma (PPAR gamma). J Biol Chem. 1995;270:12953–6.

    CAS  PubMed  Google Scholar 

  37. 37.

    Savage DB, Petersen KF, Shulman GI. Disordered lipid metabolism and the pathogenesis of insulin resistance. Physiol Rev. 2007;87:507–20.

    CAS  PubMed  PubMed Central  Google Scholar 

  38. 38.

    Tan GD, Fielding BA, Currie JM, Humphreys SM, Désage M, Frayn KN, et al. The effects of rosiglitazone on fatty acid and triglyceride metabolism in type 2 diabetes. Diabetologia. 2005;48:83–95.

    CAS  PubMed  Google Scholar 

  39. 39.

    Day C. Thiazolidinediones: a new class of antidiabetic drugs. Diabet Med. 1999;16:179–92 Review.

    CAS  PubMed  Google Scholar 

  40. 40.

    Pearson SL, Cawthorne MA, Clapham JC, Dunmore SJ, Holmes SD, Moore GB, et al. The thiazolidinedione insulin sensitiser, BRL 49653, increases the expression of PPAR-gamma and aP2 in adipose tissue of high-fat-fed rats. Biochem Biophys Res Commun. 1996;229:752–7.

    CAS  PubMed  Google Scholar 

  41. 41.

    Hansen L, Ekstrøm CT, Tabanera Y, Palacios R, Anant M, Wassermann K, et al. The Pro12Ala variant of the PPARγ gene is a risk factor for peroxisome proliferator-activated receptor-gamma/alpha agonist-induced edema in type 2 diabetic patients. J Clin Endocrinol Metab. 2006;91:3446–50.

    CAS  PubMed  Google Scholar 

  42. 42.

    Guan Y, Hao C, Cha DR, Rao R, Lu W, Kohan DE, et al. Thiazolidinediones expand body fluid volume through PPARγamma stimulation of ENaC-mediated renal salt absorption. Nat Med. 2005;11:861–6.

    CAS  PubMed  Google Scholar 

  43. 43.

    Aprile M, Cataldi S, Perfetto C, Ambrosio MR, Italiani P, Tatè R, et al. In-vitro-generated hypertrophic-like adipocytes displaying PPARG isoforms unbalance recapitulate adipocyte dysfunctions in vivo. Cells. 2020;9:1284.

    CAS  PubMed Central  Google Scholar 

  44. 44.

    Aprile M, Cataldi S, Ambrosio MR, D’Esposito V, Lim K, Dietrich A, et al. PPARγΔ5, a naturally occurring dominant-negative splice isoform, impairs PPARγ function and adipocyte differentiation. Cell Rep. 2018;25:1577–92.

    CAS  PubMed  Google Scholar 

  45. 45.

    Aprile M, Ambrosio MR, D’Esposito V, Beguinot F, Formisano P, Costa V, et al. PPARG in human adipogenesis: differential contribution of canonical transcripts and dominant negative isoforms. PPAR Res. 2014;2014:537865.

    CAS  PubMed  PubMed Central  Google Scholar 

  46. 46.

    Sabatino L, Casamassimi A, Peluso G, Barone MV, Capaccio D, Migliore C, et al. A novel peroxisome proliferator-activated receptor gamma isoform with dominant negative activity generated by alternative splicing. J Biol Chem. 2005;280:26517–25.

    CAS  PubMed  Google Scholar 

  47. 47.

    McClelland S, Shrivastava R, Medh JD. Regulation of translational efficiency by disparate 5’ UTRs of PPARgamma Splice Variants. PPAR Res. 2009;2009:193413.

    PubMed  PubMed Central  Google Scholar 

  48. 48.

    Kim HJ, Woo IS, Kang ES, Eun SY, Kim HJ, Lee JH, et al. Identification of a truncated alternative splicing variant of human PPARgamma1 that exhibits dominant negative activity. Biochem Biophys Res Commun. 2006;347:698–706.

    CAS  PubMed  Google Scholar 

  49. 49.

    He W, Barak Y, Hevener A, Olson P, Liao D, Le J, et al. Adipose-specific peroxisome proliferator-activated receptor gamma knockout causes insulin resistance in fat and liver but not in muscle. Proc Natl Acad Sci U S A. 2003;100:15712–7.

    CAS  PubMed  PubMed Central  Google Scholar 

  50. 50.

    Berger J, Leibowitz MD, Doebber TW, Elbrecht A, Zhang B, Zhou G, et al. Novel peroxisome proliferator-activated receptor (PPAR) gamma and PPARdelta ligands produce distinct biological effects. J Biol Chem. 1999;274:6718–25.

    CAS  PubMed  Google Scholar 

  51. 51.

    Costa V, Gallo MA, Letizia F, Aprile M, Casamassimi A, Ciccodicola A. PPARG: gene expression regulation and next-generation sequencing for unsolved issues. PPAR Res. 2010;2010:409168.

    PubMed  PubMed Central  Google Scholar 

  52. 52.

    Heikkinen S, Argmann C, Feige JN, Koutnikova H, Champy MF, Dali-Youcef N, et al. The Pro12Ala PPARgamma2 variant determines metabolism at the gene-environment interface. Cell Metab. 2009;9:88–98.

    CAS  PubMed  Google Scholar 

  53. 53.

    Agostini M, Schoenmakers E, Mitchell C, Szatmari I, Savage D, Smith A, et al. Non-DNA binding, dominant-negative, human PPARgamma mutations cause lipodystrophic insulin resistance. Cell Metab. 2006;4:303–11.

    CAS  PubMed  PubMed Central  Google Scholar 

  54. 54.

    Agostini M, Gurnell M, Savage DB, Wood EM, Smith AG, Rajanayagam O, et al. Tyrosine agonists reverse the molecular defects associated with dominant-negative mutations in human peroxisome proliferator-activated receptor gamma. Endocrinology. 2004;145:1527–38.

    CAS  PubMed  Google Scholar 

  55. 55.

    Al-Shali K, Cao H, Knoers N, Hermus AR, Tack CJ, Hegele RA. A single-base mutation in the peroxisome proliferator-activated receptor gamma4 promoter associated with altered in vitro expression and partial lipodystrophy. J Clin Endocrinol Metab. 2004;89:5655–60.

    CAS  PubMed  Google Scholar 

  56. 56.

    Kolehmainen M, Uusitupa MI, Alhava E, Laakso M, Vidal H. Effect of the Pro12Ala polymorphism in the peroxisome proliferator-activated receptor (PPAR) gamma2 gene on the expression of PPARgamma target genes in adipose tissue of massively obese subjects. J Clin Endocrinol Metab. 2003;88:1717–22.

    CAS  PubMed  Google Scholar 

  57. 57.

    Muller YL, Bogardus C, Beamer BA, Shuldiner AR, Baier LJ. A functional variant in the peroxisome proliferator-activated receptor gamma2 promoter is associated with predictors of obesity and type 2 diabetes in Pima Indians. Diabetes. 2003;52:1864–71.

    PubMed  Google Scholar 

  58. 58.

    Hegele RA, Cao H, Frankowski C, Mathews ST, Leff T. PPARG F388L, a transactivation-deficient mutant, in familial partial lipodystrophy. Diabetes. 2002;51:3586–90.

    CAS  PubMed  Google Scholar 

  59. 59.

    Savage DB, Agostini M, Barroso I, Gurnell M, Luan J, Meirhaeghe A, et al. Digenic inheritance of severe insulin resistance in a human pedigree. Nat Genet. 2002;31:379–84.

    CAS  PubMed  Google Scholar 

  60. 60.

    Deeb SS, Fajas L, Nemoto M, Pihlajamäki J, Mykkänen L, Kuusisto J, et al. A Pro12Ala substitution in PPARgamma2 associated with decreased receptor activity, lower body mass index and improved insulin sensitivity. Nat Genet. 1998;20:284–7.

    CAS  PubMed  Google Scholar 

  61. 61.

    Barroso I, Gurnell M, Crowley VE, Agostini M, Schwabe JW, Soos MA, et al. Dominant negative mutations in human PPARgamma associated with severe insulin resistance, diabetes mellitus and hypertension. Nature. 1999;402:880–3.

    CAS  PubMed  Google Scholar 

  62. 62.

    Masugi J, Tamori Y, Mori H, Koike T, Kasuga M. Inhibitory effect of a proline-to-alanine substitution at codon 12 of peroxisome proliferator-activated receptor-gamma 2 on thiazolidinedione-induced adipogenesis. Biochem Biophys Res Commun. 2000;268:178–82.

    CAS  PubMed  Google Scholar 

  63. 63.

    Pollastro C, Ziviello C, Costa V, Ciccodicola A. Pharmacogenomics of drug response in type 2 diabetes: toward the definition of tailored therapies? PPAR Res. 2015;2015:415149.

    PubMed  PubMed Central  Google Scholar 

  64. 64.

    Yen CJ, Beamer BA, Negri C, Silver K, Brown KA, Yarnall DP, et al. Molecular scanning of the human peroxisome proliferator activated receptor gamma (hPPAR gamma) gene in diabetic Caucasians: identification of a Pro12Ala PPAR gamma 2 missense mutation. Biochem Biophys Res Commun. 1997;241:270–4.

    CAS  PubMed  Google Scholar 

  65. 65.

    Altshuler D, Hirschhorn JN, Klannemark M, Lindgren CM, Vohl MC, Nemesh J, et al. The common PPARgamma Pro12Ala polymorphism is associated with decreased risk of type 2 diabetes. Nat Genet. 2000;26:76–80.

    CAS  PubMed  Google Scholar 

  66. 66.

    Sarhangi N, Sharifi F, Hashemian L, Hassani Doabsari M, Heshmatzad K, Rahbaran M, et al. PPARG (Pro12Ala) genetic variant and risk of T2DM: a systematic review and meta-analysis. Sci Rep. 2020;10:12764.

    CAS  PubMed  PubMed Central  Google Scholar 

  67. 67.

    Galbete C, Toledo E, Martínez-González MA, Martínez JA, Guillén-Grima F, Marti A. Pro12Ala variant of the PPARG2 gene increases body mass index: an updated meta-analysis encompassing 49,092 subjects. Obesity (Silver Spring). 2013;21:1486–95.

    CAS  Google Scholar 

  68. 68.

    Stryjecki C, Peralta-Romero J, Alyass A, et al. Association between PPAR-γ2 Pro12Ala genotype and insulin resistance is modified by circulating lipids in Mexican children. Sci Rep. 2016;6:24472.

    CAS  PubMed  PubMed Central  Google Scholar 

  69. 69.

    Mansoori A, Amini M, Kolahdooz F, Seyedrezazadeh E. Obesity and Pro12Ala polymorphism of peroxisome proliferator-activated receptor-gamma gene in healthy adults: a systematic review and meta-analysis. Ann Nutr Metab. 2015;67:104–18.

    CAS  PubMed  Google Scholar 

  70. 70.

    Lindi VI, Uusitupa MI, Lindström J, Louheranta A, Eriksson JG, Valle TT, et al. Association of the Pro12Ala polymorphism in the PPAR-gamma2 gene with 3-year incidence of type 2 diabetes and body weight change in the Finnish Diabetes Prevention Study. Diabetes. 2002;51:2581–6.

    CAS  PubMed  Google Scholar 

  71. 71.

    Masud S, Ye S, SAS Group. Effect of the peroxisome proliferator activated receptor-gamma gene Pro12Ala variant on body mass index: a meta-analysis. J Med Genet. 2003;40:773–80.

    CAS  PubMed  PubMed Central  Google Scholar 

  72. 72.

    Costa V, Casamassimi A, Ciccodicola A. Nutritional genomics era: opportunities toward a genome-tailored nutritional regimen. J Nutr Biochem. 2010;21:457–67.

    CAS  PubMed  Google Scholar 

  73. 73.

    Gray N, Picone G, Sloan Y. The relationship between BMI and onset of diabetes mellitus and its complications. South Med J. 2015;108:29–36.

    PubMed  PubMed Central  Google Scholar 

  74. 74.

    Tönjes A, Scholz M, Loeffler M, Stumvoll M. Association of Pro12Ala polymorphism in peroxisome proliferator-activated receptor gamma with Pre-diabetic phenotypes: meta-analysis of 57 studies on nondiabetic individuals. Diabetes Care. 2006;29:2489–97.

    PubMed  Google Scholar 

  75. 75.

    Takata N, Awata T, Inukai K, Watanabe M, Ohkubo T, Kurihara S, et al. Pro12Ala substitution in peroxisome proliferator-activated receptor gamma 2 is associated with low adiponectin concentrations in young Japanese men. Metabolism. 2004;53:1548–51.

    CAS  PubMed  Google Scholar 

  76. 76.

    Yamamoto Y, Hirose H, Miyashita K, Nishikai K, Saito I, Taniyama M, et al. PPAR(gamma)2 gene Pro12Ala polymorphism may influence serum level of an adipocyte-derived protein, adiponectin, in the Japanese population. Metabolism. 2002;51:1407–9.

    CAS  PubMed  Google Scholar 

  77. 77.

    Hegele RA, Cao H, Harris SB, Zinman B, Hanley AJ, Anderson CM. Peroxisome proliferator-activated receptor-gamma2 P12A and type 2 diabetes in Canadian Oji-Cree. J Clin Endocrinol Metab. 2000;85:2014–9.

    CAS  PubMed  Google Scholar 

  78. 78.

    Evans D, de Heer J, Hagemann C, Wendt D, Wolf A, Beisiegel U, et al. Association between the P12A and c1431t polymorphisms in the peroxisome proliferator activated receptor gamma (PPAR gamma) gene and type 2 diabetes. Exp Clin Endocrinol Diabetes. 2001;109:151–4.

    CAS  PubMed  Google Scholar 

  79. 79.

    Hasstedt SJ, Ren QF, Teng K, Elbein SC. Effect of the peroxisome proliferator-activated receptor-gamma 2 pro(12)ala variant on obesity, glucose homeostasis, and blood pressure in members of familial type 2 diabetic kindreds. J Clin Endocrinol Metab. 2001;86:536–41.

    CAS  PubMed  Google Scholar 

  80. 80.

    Engwa GA, Nwalo FN, Chiezey VO, Unachukwu MN, Ojo OO, Ubi BE. Assessment of the Pro12Ala polymorphism in the PPAR-γ2 gene among type 2 diabetes patients in a Nigerian population. J Clin Med. 2018;7:69.

    PubMed Central  Google Scholar 

  81. 81.

    Chistiakov DA, Potapov VA, Khodirev DS, Shamkhalova MS, Shestakova MV, Nosikov VV. The PPARgamma Pro12Ala variant is associated with insulin sensitivity in Russian normoglycaemic and type 2 diabetic subjects. Diab Vasc Dis Res. 2010;7:56–62.

    PubMed  Google Scholar 

  82. 82.

    Gouda HN, Sagoo GS, Harding AH, Yates J, Sandhu MS, Higgins JP. The association between the peroxisome proliferator-activated receptor-gamma2 (PPARG2) Pro12Ala gene variant and type 2 diabetes mellitus: a HuGE review and meta-analysis. Am J Epidemiol. 2010;171:645–55.

    PubMed  PubMed Central  Google Scholar 

  83. 83.

    Mohamed MB, Mtiraoui N, Ezzidi I, Chaieb M, Mahjoub T, Almawi WY. Association of the peroxisome proliferator-activated receptor-gamma2 Pro12Ala but not the C1431T gene variants with lower body mass index in Type 2 diabetes. J Endocrinol Invest. 2007;30:937–43.

    PubMed  Google Scholar 

  84. 84.

    Radha V, Vimaleswaran KS, Babu S, Deepa R, Anjana M, Ghosh S, et al. Lack of association between serum adiponectin levels and the Pro12Ala polymorphism in Asian Indians. Diabet Med. 2007;24:398–402.

    CAS  PubMed  Google Scholar 

  85. 85.

    Doney ASF, Fischer B, Cecil JE, Boylan K, McGuigan FE, Ralston SH, et al. Association of the Pro12Ala and C1431T variants of PPARG and their haplotypes with susceptibility to type 2 diabetes. Diabetologia. 2004;47:555–8.

    CAS  PubMed  Google Scholar 

  86. 86.

    Wang C, Zhai F, Chi Y, Wang G. Association of Pro12Ala mutation in peroxisome proliferator-activated receptor gamma 2 with obesity and diabetes in Chinese population. Wei Sheng Yan Jiu. 2004;33:317–20 Chinese.

    CAS  PubMed  Google Scholar 

  87. 87.

    Mori H, Ikegami H, Kawaguchi Y, Seino S, Yokoi N, Takeda J, et al. The Pro12 Ala substitution in PPAR-gamma is associated with resistance to development of diabetes in the general population: possible involvement in impairment of insulin secretion in individuals with type 2 diabetes. Diabetes. 2001;50:891–4.

    CAS  PubMed  Google Scholar 

  88. 88.

    Mancini FP, Vaccaro O, Sabatino L, Tufano A, Rivellese AA, Riccardi G, et al. Pro12-->Ala substitution in the peroxisome proliferator-activated receptor-gamma2 is not associated with type 2 diabetes. Diabetes. 1999;48:1466–8.

    CAS  PubMed  Google Scholar 

  89. 89.

    Luan J, Browne PO, Harding AH, Halsall DJ, O’Rahilly S, Chatterjee VK, et al. Evidence for gene-nutrient interaction at the PPARγamma locus. Diabetes. 2001;50:686–9.

    CAS  PubMed  Google Scholar 

  90. 90.

    Caramori ML, Canani LH, Costa LA, Gross JL. The human peroxisome proliferator activated receptor gamma2 (PPARgamma2) Pro12Ala polymorphism is associated with decreased risk of diabetic nephropathy in patients with type 2 diabetes. Diabetes. 2003;52:3010–3.

    CAS  PubMed  Google Scholar 

  91. 91.

    Herrmann SM, Ringel J, Wang JG, Staessen JA, Brand E, Berlin Diabetes Mellitus (BeDiaM) Study. Peroxisome proliferator-activated receptor-gamma2 polymorphism Pro12Ala is associated with nephropathy in type 2 diabetes: the Berlin Diabetes Mellitus (BeDiaM) Study. Diabetes. 2002;51:2653-7.

    PubMed  Google Scholar 

  92. 92.

    Morris AP, Voight BF, Teslovich TM, et al. Large-scale association analysis provides insights into the genetic architecture and pathophysiology of type 2 diabetes. Nat Genet. 2012;44:981–90.

    CAS  PubMed  PubMed Central  Google Scholar 

  93. 93.

    Liu L, Zheng T, Wang F, Wang N, Song Y, Li M, et al. Pro12Ala polymorphism in the PPARG gene contributes to the development of diabetic nephropathy in Chinese type 2 diabetic patients. Diabetes Care. 2010;33:144–9.

    CAS  PubMed  Google Scholar 

  94. 94.

    Zheng TY, Lin YJ, Horng JC. Thermodynamic consequences of incorporating 4-substituted proline derivatives into a small helical protein. Biochemistry. 2010;49:4255–63.

    CAS  PubMed  Google Scholar 

  95. 95.

    Hamann A, Münzberg H, Buttron P, Büsing B, Hinney A, Mayer H, et al. Missense variants in the human peroxisome proliferator-activated receptor-gamma2 gene in lean and obese subjects. Eur J Endocrinol. 1999;141:90–2.

    CAS  PubMed  Google Scholar 

  96. 96.

    Hansen L, Ekstrøm CT, Tabanera Y, Palacios R, Anant M, Wassermann K, et al. The Pro12Ala variant of the PPARG gene is a risk factor for peroxisome proliferator-activated receptor-gamma/alpha agonist-induced edema in type 2 diabetic patients. J Clin Endocrinol Metab. 2006;91:3446–50.

    CAS  PubMed  Google Scholar 

  97. 97.

    Snitker S, Watanabe RM, Ani I, Xiang AH, Marroquin A, Ochoa C, et al. Changes in insulin sensitivity in response to troglitazone do not differ between subjects with and without the common, functional Pro12Ala peroxisome proliferator-activated receptor-gamma2 gene variant: results from the Troglitazone in Prevention of Diabetes (TRIPOD) study. Diabetes Care. 2004;27:1365-8.

    PubMed  Google Scholar 

  98. 98.

    Blüher M, Lübben G, Paschke R. Analysis of the relationship between the Pro12Ala variant in the PPAR-gamma2 gene and the response rate to therapy with pioglitazone in patients with type 2 diabetes. Diabetes Care. 2003;26:825–31.

    PubMed  Google Scholar 

  99. 99.

    Hsieh MC, Lin KD, Tien KJ, et al. Common polymorphisms of the peroxisome proliferator-activated receptor-gamma (Pro12Ala) and peroxisome proliferator-activated receptor-gamma coactivator-1 (Gly482Ser) and the response to pioglitazone in Chinese patients with type 2 diabetes mellitus. Metabolism. 2010;59:1139–44.

    CAS  PubMed  Google Scholar 

  100. 100.

    Kang ES, Park SY, Kim HJ, et al. Effects of Pro12Ala polymorphism of peroxisome proliferator-activated receptor gamma2 gene on rosiglitazone response in type 2 diabetes. Clin Pharmacol Ther. 2005;78:202–8.

    CAS  PubMed  Google Scholar 

  101. 101.

    Florez JC, Jablonski KA, Sun MW, Bayley N, Kahn SE, Shamoon H, et al. Altshuler D; Diabetes Prevention Program Research Group. Effects of the type 2 diabetes-associated PPARG P12A polymorphism on progression to diabetes and response to troglitazone. J Clin Endocrinol Metab. 2007 Apr;92(4):1502–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  102. 102.

    Costa V, Casamassimi A, Esposito K, Villani A, Capone M, Iannella R, et al. Characterization of a novel polymorphism in PPARG regulatory region associated with type 2 diabetes and diabetic retinopathy in Italy. J Biomed Biotechnol. 2009;2009:126917.

    PubMed  Google Scholar 

  103. 103.

    Vigouroux C, Fajas L, Khallouf E, Meier M, Gyapay G, Lascols O, 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. Diabetes. 1998;47:490–2.

    CAS  PubMed  Google Scholar 

  104. 104.

    Okazawa H, Mori H, Tamori Y, et al. No coding mutations are detected in the peroxisome proliferator-activated receptor-gamma gene in Japanese patients with lipoatrophic diabetes. Diabetes. 1997;46:1904–6.

    CAS  PubMed  Google Scholar 

  105. 105.

    Wu Y, Zhu Y, Fan W. The association of PPARγ C1431T polymorphism with susceptibility to type 2 diabetes: a systemic review and meta-analysis. Int J Clin Exp Med. 2017;10:4313–8.

    CAS  Google Scholar 

  106. 106.

    Butt H, Shabana, Hasnain S. The C1431T polymorphism of peroxisome proliferator acti- vated receptor gamma (PPAR gamma) is associated with low risk of diabetes in a Pakistani cohort. Diabetol Metab Syndr. 2016;8:67.

    PubMed  PubMed Central  Google Scholar 

  107. 107.

    Agostini M, Schoenmakers E, Beig J, Fairall L, Szatmari I, Rajanayagam O, et al. A pharmacogenetic approach to the treatment of patients With PPARGmutations. Diabetes. 2018;67:1086–92.

    CAS  PubMed  PubMed Central  Google Scholar 

  108. 108.

    Demir T, Onay H, Savage DB, et al. Familial partial lipodystrophy linked to a novel peroxisome proliferator activator receptor -γ (PPARγ) mutation, H449L: a comparison of people with this mutation and those with classic codon 482 Lamin A/C (LMNA) mutations. Diabet Med. 2016;33:1445–50.

    CAS  PubMed  Google Scholar 

  109. 109.

    Majithia AR, Tsuda B, Agostini M, Gnanapradeepan K, Rice R, Peloso G, et al. Prospective functional classification of all possible missense variants in PPARG. Nat Genet. 2016;48:1570–5.

    CAS  PubMed  PubMed Central  Google Scholar 

  110. 110.

    Majithia AR, Flannick J, Shahinian P, Guo M, Bray MA, Fontanillas P, et al. Rare variants in PPARG with decreased activity in adipocyte differentiation are associated with increased risk of type 2 diabetes. Proc Natl Acad Sci U S A. 2014;111:13127–32.

    CAS  PubMed  PubMed Central  Google Scholar 

  111. 111.

    Savage DB, Tan GD, Acerini CL, et al. Human metabolic syndrome resulting from dominant-negative mutations in the nuclear receptor peroxisome proliferator-activated receptor-gamma. Diabetes. 2003;52:910–7.

    CAS  PubMed  Google Scholar 

  112. 112.

    Agarwal AK, Garg A. A novel heterozygous mutation in peroxisome proliferator-activated receptor-gamma gene in a patient with familial partial lipodystrophy. J Clin Endocrinol Metab. 2002;87:408–11.

    CAS  PubMed  Google Scholar 

  113. 113.

    Ristow M, Müller-Wieland D, Pfeiffer A, Krone W, Kahn CR. Obesity associated with a mutation in a genetic regulator of adipocyte differentiation. N Engl J Med. 1998;339:953–9.

    CAS  PubMed  Google Scholar 

  114. 114.

    Blüher M, Paschke R. Analysis of the relationship between PPAR-gamma 2 gene variants and severe insulin resistance in obese patients with impaired glucose tolerance. Exp Clin Endocrinol Diabetes. 2003;111:85–90.

    PubMed  Google Scholar 

  115. 115.

    Agústsson TT, Hákonarson H, Olafsson I, Hjaltadóttir G, Thornórsson AV. A mutation detection in a transcription factor for adipocyte development in children with severe obesity. Laeknabladid. 2001;87:119–24 Icelandic.

    PubMed  Google Scholar 

  116. 116.

    Shuldiner AR, Nguyen W, Kao WH, et al. Pro115Gln peroxisome proliferator-activated receptor-gamma and obesity. Diabetes Care. 2000;23:126–7.

    CAS  PubMed  Google Scholar 

  117. 117.

    Clement K, Hercberg S, Passinge B, Galan P, Varroud-Vial M, Shuldiner AR, et al. The Pro115Gln and Pro12Ala PPAR gamma gene mutations in obesity and type 2 diabetes. Int J Obes Relat Metab Disord. 2000;24:391–3.

    CAS  PubMed  Google Scholar 

  118. 118.

    Li G, Leff T. Altered promoter recycling rates contribute to dominant-negative activity of human peroxisome proliferator- activated receptor-gamma mutations associated with diabetes. Mol. Endocrinol. 2007;21:857–64.

    CAS  PubMed  Google Scholar 

  119. 119.

    Francis GA, Li G, Casey R, Wang J, Cao H, Leff T, et al. Peroxisomal proliferator activated receptor-gamma deficiency in a Canadian kindred with familial partial lipodystrophy type 3 (FPLD3). BMC Med Genet. 2006;7:3.

    PubMed  PubMed Central  Google Scholar 

  120. 120.

    Brunmeir R, Xu F. Functional regulation of PPARs through post-translational modifications. Int J Mol Sci. 2018;19:1738.

    PubMed Central  Google Scholar 

  121. 121.

    Banks AS, McAllister FE, Camporez JP, Zushin PJ, Jurczak MJ, Laznik-Bogoslavski D, et al. An ERK/Cdk5 axis controls the diabetogenic actions of PPARγ. Nature. 2015;517:391–5.

    CAS  PubMed  Google Scholar 

  122. 122.

    van Beekum O, Fleskens V, Kalkhoven E. Posttranslational modifications of PPAR-gamma: fine-tuning the metabolic master regulator. Obesity (Silver Spring). 2009;17:213–9.

    Google Scholar 

  123. 123.

    Burns KA, Vanden Heuvel JP. Modulation of PPAR activity via phosphorylation. Biochim Biophys Acta. 2007 Aug;1771(8):952–60.

    CAS  PubMed  PubMed Central  Google Scholar 

  124. 124.

    Yin R, Dong YG, Li HL. PPARgamma phosphorylation mediated by JNK MAPK: a potential role in macrophage-derived foam cell formation. Acta Pharmacol Sin. 2006;27:1146–52.

    CAS  PubMed  Google Scholar 

  125. 125.

    Leff T. AMP-activated protein kinase regulates gene expression by direct phosphorylation of nuclear proteins. Biochem Soc Trans. 2003;31:224–7.

    CAS  PubMed  Google Scholar 

  126. 126.

    Han J, Hajjar DP, Tauras JM, Feng J, Gotto AM Jr, Nicholson AC. Transforming growth factor-beta1 (TGF-beta1) and TGF-beta2 decrease expression of CD36, the type B scavenger receptor, through mitogen-activated protein kinase phosphorylation of peroxisome proliferator-activated receptor-gamma. J Biol Chem. 2000;275:1241–6.

    CAS  PubMed  Google Scholar 

  127. 127.

    Shao DL, Rangwala SM, Bailey ST, Krakow SL, Reginato MJ, Lazar MA. Interdomain communication regulating ligand binding by PPAR-gamma. Nature. 1998;396:377–80.

    CAS  PubMed  Google Scholar 

  128. 128.

    Adams M, Reginato MJ, Shao D, Lazar MA, Chatterjee VK. Transcriptional activation by peroxisome proliferator-activated receptor gamma is inhibited by phosphorylation at a consensus mitogen-activated protein kinase site. J Biol Chem. 1997;272:5128–32.

    CAS  PubMed  Google Scholar 

  129. 129.

    Camp HS, Tafuri SR. Regulation of peroxisome proliferator-activated receptor gamma activity by mitogen-activated protein kinase. J Biol Chem. 1997 Apr 18;272(16):10811–6.

    CAS  PubMed  Google Scholar 

  130. 130.

    Hu E, Kim JB, Sarraf P, Spiegelman BM. Inhibition of adipogenesis through MAP kinase-mediated phosphorylation of PPARgamma. Science. 1996 Dec 20;274(5295):2100–3.

    CAS  PubMed  Google Scholar 

  131. 131.

    Hotamisligil GS, Arner P, Caro JF, Atkinson RL, Spiegelman BM. Increased adipose tissue expression of tumor necrosis factor-alpha in human obesity and insulin resistance. J Clin Invest. 1995;95:2409–15.

    CAS  PubMed  PubMed Central  Google Scholar 

  132. 132.

    Anbalagan M, Huderson B, Murphy L, Rowan BG. Post-translational modifications of nuclear receptors and human disease. Nucl Recept Signal. 2012;10:e001.

    CAS  PubMed  PubMed Central  Google Scholar 

  133. 133.

    Jurkowski W, Roomp K, Crespo I, Schneider JG, Del Sol A. PPARγ population shift produces disease-related changes in molecular networks associated with metabolic syndrome. Cell Death Dis. 2011 Aug 11;2(8):e192.

    CAS  PubMed  PubMed Central  Google Scholar 

  134. 134.

    Choi JH, Choi SS, Kim ES, et al. Thrap3 docks on phosphoserine 273 of PPARγ and controls diabetic gene programming. Genes Dev. 2014;28:2361–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  135. 135.

    Li P, Fan W, Xu J, et al. Adipocyte NCoR knockout decreases PPARγ phosphorylation and enhances PPARγ activity and insulin sensitivity. Cell. 2011;147:815–26.

    CAS  PubMed  PubMed Central  Google Scholar 

  136. 136.

    Dhavan R, Tsai LH. A decade of CDK5. Nat Rev Mol Cell Biol. 2001;2:749–59.

    CAS  PubMed  Google Scholar 

  137. 137.

    Hall JA, Ramachandran D, Roh HC, DiSpirito JR, Belchior T, Zushin PH, et al. Obesity-linked PPARγ S273 phosphorylation promotes insulin resistance through growth differentiation factor 3. Cell Metab. 2020;32(4):665–675.e6.

    CAS  PubMed  Google Scholar 

  138. 138.

    Choi JH, Banks AS, Kamenecka TM, Busby SA, Chalmers MJ, Kumar N, et al. Antidiabetic actions of a non-agonist PPARγ ligand blocking Cdk5-mediated phosphorylation. Nature. 2011 Sep 4;477(7365):477–81.

    CAS  PubMed  PubMed Central  Google Scholar 

  139. 139.

    Wright MB, Bortolini M, Tadayyon M, Bopst M. Minireview: Challenges and opportunities in development of PPAR agonists. Mol Endocrinol. 2014;28:1756–68.

    PubMed  PubMed Central  Google Scholar 

  140. 140.

    Mori H, Okada Y, Arao T, Nishida K, Tanaka Y. Telmisartan at 80 mg/day increases high-molecular-weight adiponectin levels and improves insulin resistance in diabetic patients. Adv Ther. 2012;29:635–44.

    CAS  PubMed  Google Scholar 

  141. 141.

    Ma L, Ji JL, Ji H, Yu X, Ding LJ, Liu K, et al. Telmisartan alleviates rosiglitazone-induced bone loss in ovariectomized spontaneous hypertensive rats. Bone. 2010;47:5–11.

    CAS  PubMed  Google Scholar 

  142. 142.

    Tagami T, Yamamoto H, Moriyama K, Sawai K, Usui T, Shimatsu A, et al. A selective peroxisome proliferator-activated receptor-gamma modulator, telmisartan, binds to the receptor in a different fashion from thiazolidinediones. Endocrinology. 2009;150:862–70.

    CAS  PubMed  Google Scholar 

  143. 143.

    Henriksen EJ, Jacob S, Kinnick TR, Teachey MK, Krekler M. Selective angiotensin II receptor antagonism reduces insulin resistance in obese Zucker rats. Hypertension. 2001;38:884–90.

    CAS  PubMed  Google Scholar 

  144. 144.

    El Ouarrat D, Isaac R, Lee YS, Oh DY, Wollam J, Lackey D, et al. TAZ is a negative regulator of PPARγ activity in adipocytes and TAZ deletion improves insulin sensitivity and glucose tolerance. Cell Metab. 2020;31:162–173.e5.

    PubMed  Google Scholar 

  145. 145.

    Qiang L, Wang L, Kon N, Zhao W, Lee S, Zhang Y, et al. Brown remodeling of white adipose tissue by SirT1-dependent deacetylation of Pparγ. Cell. 2012;150:620–32.

    CAS  PubMed  PubMed Central  Google Scholar 

  146. 146.

    Wang H, Qiang L, Farmer SR. Identification of a domain within peroxisome proliferator-activated receptor gamma regulating expression of a group of genes containing fibroblast growth factor 21 that are selectively repressed by SIRT1 in adipocytes. Mol Cell Biol. 2008;28:188–200.

    PubMed  Google Scholar 

  147. 147.

    Wang H, Liu L, Lin JZ, Aprahamian TR, Farmer SR. Browning of white adipose tissue with roscovitine induces a distinct population of UCP1+ Adipocytes. Cell Metab. 2016 Dec 13;24(6):835–47.

    CAS  PubMed  PubMed Central  Google Scholar 

  148. 148.

    Han L, Zhou R, Niu J, McNutt MA, Wang P, Tong T. SIRT1 is regulated by a PPAR{γ}-SIRT1 negative feedback loop associated with senescence. Nucleic Acids Res. 2010;38:7458–71.

    CAS  PubMed  PubMed Central  Google Scholar 

  149. 149.

    Hietakangas V, Anckar J, Blomster HA, Fujimoto M, Palvimo JJ, Nakai A, et al. PDSM, a motif for phosphorylation-dependent SUMO modification. Proc Natl Acad Sci USA. 2006;103:45–50.

    CAS  PubMed  Google Scholar 

  150. 150.

    Yang XJ, Grégoire S. A recurrent phospho-sumoyl switch in transcriptional repression and beyond. Mol Cell. 2006;23:779–86 Erratum in: Mol Cell. 2006;24:635.

    PubMed  Google Scholar 

  151. 151.

    Yamashita D, Yamaguchi T, Shimizu M, Nakata N, Hirose F, Osumi T. The transactivating function of peroxisome proliferator-activated receptor gamma is negatively regulated by SUMO conjugation in the amino-terminal domain. Genes Cells. 2004 Nov;9(11):1017–29.

    CAS  PubMed  Google Scholar 

  152. 152.

    Ohshima T, Koga H, Shimotohno K. Transcriptional activity of peroxisome proliferator-activated receptor gamma is modulated by SUMO-1 modification. J Biol Chem. 2004;279:29551–7.

    CAS  PubMed  Google Scholar 

  153. 153.

    Chung SS, Ahn BY, Kim M, et al. Control of adipogenesis by the SUMO-specific protease SENP2. Mol Cell Biol. 2010;30:2135–46.

    CAS  PubMed  PubMed Central  Google Scholar 

  154. 154.

    Rytinki MM, Palvimo JJ. SUMOylation attenuates the function of PGC-1alpha. J Biol Chem. 2009;284:26184–93.

    CAS  PubMed  PubMed Central  Google Scholar 

  155. 155.

    Floyd ZE, Stephens JM. Interferon-gamma-mediated activation and ubiquitin-proteasome-dependent degradation of PPARgamma in adipocytes. J Biol Chem. 2002;277(6):4062–8.

    CAS  PubMed  Google Scholar 

  156. 156.

    Hauser S, Adelmant G, Sarraf P, Wright HM, Mueller E, Spiegelman BM. Degradation of the peroxisome proliferator-activated receptor gamma is linked to ligand-dependent activation. J Biol Chem. 2000;275(24):18527–33.

    CAS  PubMed  Google Scholar 

  157. 157.

    Praefcke GJ, Hofmann K, Dohmen RJ. SUMO playing tag with ubiquitin. Trends Biochem Sci. 2012;37:23–31.

    CAS  PubMed  Google Scholar 

  158. 158.

    Zhu K, Tang Y, Xu X, Dang H, Tang LY, Wang X, et al. Non-proteolytic ubiquitin modification of PPARγ by Smurf1 protects the liver from steatosis. PLoS Biol. 2018;16:e3000091.

    CAS  PubMed  PubMed Central  Google Scholar 

  159. 159.

    Li P, Song Y, Zan W, Qin L, Han S, Jiang B, et al. Lack of CUL4B in adipocytes promotes PPARγ-mediated adipose tissue expansion and insulin sensitivity. Diabetes. 2017;66:300–13.

    CAS  PubMed  Google Scholar 

  160. 160.

    Lee KW, Kwak SH, Koo YD, et al. F-box only protein 9 is an E3 ubiquitin ligase of PPARγ. Exp Mol Med. 2016;48:e234.

    CAS  PubMed  PubMed Central  Google Scholar 

  161. 161.

    Wei S, Yang J, Lee SL, Kulp SK, Chen CS. PPARgamma-independent antitumor effects of thiazolidinediones. Cancer Lett. 2009;276:119–24.

    CAS  PubMed  Google Scholar 

  162. 162.

    Wei S, Yang HC, Chuang HC, Yang J, Kulp SK, Lu PJ, et al. A novel mechanism by which thiazolidinediones facilitate the proteasomal degradation of cyclin D1 in cancer cells. J Biol Chem. 2008;283:26759–70.

    CAS  PubMed  PubMed Central  Google Scholar 

  163. 163.

    Wang CC, Wang YC, Wei S, Lin LF, Chen CS, Lee CC, et al. Peroxisome proliferator-activated receptor gamma-independent suppression of androgen receptor expression by troglitazone mechanism and pharmacologic exploitation. Cancer Res. 2007;67:3229–38.

    PubMed  Google Scholar 

  164. 164.

    Moldes M, Zuo Y, Morrison RF, Silva D, Park BH, Liu J, et al. Peroxisome-proliferator-activated receptor gamma suppresses Wnt/beta-catenin signalling during adipogenesis. Biochem J. 2003;376:607–13.

    CAS  PubMed  PubMed Central  Google Scholar 

  165. 165.

    Kim Y, Suh N, Sporn M, Reed CJ. An inducible pathway for degradation of FLIP protein sensitizes tumor cells to TRAIL-induced apoptosis. J Biol Chem. 2002;277:22320–9.

    CAS  PubMed  Google Scholar 

  166. 166.

    Wang C, Fu M, D’Amico M, Albanese C, Zhou JN, Brownlee M, et al. Inhibition of cellular proliferation through IkappaB kinase-independent and peroxisome proliferator-activated receptor gamma-dependent repression of cyclin D1. Mol Cell Biol. 2001;21:3057–70.

    CAS  PubMed  PubMed Central  Google Scholar 

  167. 167.

    Dutchak PA, Katafuchi T, Bookout AL, Choi JH, Yu RT, Mangelsdorf DJ, et al. Fibroblast growth factor-21 regulates PPARγ activity and the antidiabetic actions of thiazolidinediones. Cell. 2012;148:556–67.

    CAS  PubMed  PubMed Central  Google Scholar 

  168. 168.

    Ricote M, Glass CK. PPARs and molecular mechanisms of transrepression. Biochim Biophys Acta. 1771;2007:926–35.

    Google Scholar 

  169. 169.

    Shimizu M, Yamashita D, Yamaguchi T, Hirose F, Osumi T. Aspects of the regulatory mechanisms of PPAR functions: analysis of a bidirectional response element and regulation by sumoylation. Mol Cell Biochem. 2006 Jun;286(1-2):33–42.

    CAS  PubMed  Google Scholar 

  170. 170.

    Ghisletti S, Huang W, Ogawa S, Pascual G, Lin ME, Willson TM, et al. Parallel SUMOylation-dependent pathways mediate gene- and signal-specific transrepression by LXRs and PPARγamma. Mol Cell. 2007;25:57–70.

    CAS  PubMed  PubMed Central  Google Scholar 

  171. 171.

    Mikkonen L, Hirvonen J, Jänne OA. SUMO-1 regulates body weight and adipogenesis via PPARγ in male and female mice. Endocrinology. 2013;154:698–708.

    CAS  PubMed  Google Scholar 

  172. 172.

    Ji S, Park SY, Roth J, Kim HS, Cho JW. O-GlcNAc modification of PPARγ reduces its transcriptional activity. Biochem Biophys Res Commun. 2012;417:1158–63.

    CAS  PubMed  Google Scholar 

  173. 173.

    Yang YR, Jang HJ, Choi SS, Lee YH, Lee GH, Seo YK, et al. Obesity resistance and increased energy expenditure by white adipose tissue browning in Oga(+/-) mice. Diabetologia. 2015;58:2867–76.

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We acknowledge EFSD/Boehringer Ingelheim European Research Programme in Microvascular Complications of Diabetes, granted to A.C. and funding M.A. research contract, and PON Ricerca e Innovazione 2014–2020, PON Ars01_01270 “Innovative Device For SHAping the Risk of Diabetes” (IDF SHARID) to V.C.

Author information

Affiliations

Authors

Corresponding author

Correspondence to Alfredo Ciccodicola.

Ethics declarations

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

Conflict of Interest

The authors declare no competing interests.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

This article is part of the Topical Collection on Genetics

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Cataldi, S., Costa, V., Ciccodicola, A. et al. PPARγ and Diabetes: Beyond the Genome and Towards Personalized Medicine. Curr Diab Rep 21, 18 (2021). https://doi.org/10.1007/s11892-021-01385-5

Download citation

Keywords

  • PPARG genetic variants
  • Dominant-negative isoforms
  • Post-tranlational modifications
  • Adipose tissue dysfunctions
  • Drug responsiveness
  • Type 2 diabetes