Artículos de revistas
Gq-16, A Novel Peroxisome Proliferator-activated Receptor γ (pparγ) Ligand, Promotes Insulin Sensitization Without Weight Gain
Registro en:
Journal Of Biological Chemistry. , v. 287, n. 33, p. 28169 - 28179, 2012.
219258
10.1074/jbc.M111.332106
2-s2.0-84864976082
Autor
Amato A.A.
Rajagopalan S.
Lin J.Z.
Carvalho B.M.
Figueira A.C.M.
Lu J.
Ayers S.D.
Mottin M.
Silveira R.L.
Souza P.C.T.
Mourao R.H.V.
Saad M.J.A.
Togashi M.
Simeoni L.A.
Abdalla D.S.P.
Skaf M.S.
Polikparpov I.
Lima M.C.A.
Galdino S.L.
Brennan R.G.
Baxter J.D.
Pitta I.R.
Webb P.
Phillips K.J.
Neves F.A.R.
Institución
Resumen
The recent discovery that peroxisome proliferator-activated receptor γ (PPARγ) targeted anti-diabetic drugs function by inhibiting Cdk5-mediated phosphorylation of the receptor has provided a new viewpoint to evaluate and perhaps develop improved insulin-sensitizing agents. Herein we report the development of a novel thiazolidinedione that retains similar anti-diabetic efficacy as rosiglitazone in mice yet does not elicit weight gain or edema, common side effects associated with full PPARγ activation. Further characterization of this compound shows GQ-16 to be an effective inhibitor of Cdk5-mediated phosphorylation of PPARγ. The structure of GQ-16 bound to PPARγ demonstrates that the compound utilizes a binding mode distinct from other reported PPARγ ligands, although it does share some structural features with other partial agonists, such as MRL-24 and PA-082, that have similarly been reported to dissociate insulin sensitization from weight gain. Hydrogen/deuterium exchange studies reveal that GQ-16 strongly stabilizes the β-sheet region of the receptor, presumably explaining the compound's efficacy in inhibiting Cdk5-mediated phosphorylation of Ser-273. Molecular dynamics simulations suggest that the partial agonist activity of GQ-16 results from the compound's weak ability to stabilize helix 12 in its active conformation. Our results suggest that the emerging model, whereby "ideal" PPARγ-based therapeutics stabilize the β-sheet/Ser-273 region and inhibit Cdk5-mediated phosphorylation while minimally invoking adipogenesis and classical agonism, is indeed a valid framework to develop improved PPARγ modulators that retain antidiabetic actions while minimizing untoward effects. © 2012 by The American Society for Biochemistry and Molecular Biology, Inc. 287 33 28169 28179 Lehmann, J.M., Moore, L.B., Smith-Oliver, T.A., Wilkison, W.O., Willson, T.M., Kliewer, S.A., An antidiabetic thiazolidinedione is a high affinity ligand for peroxisome proliferator-activated receptor γ (PPARγ) (1995) J. Biol. Chem., 270, pp. 12953-12956 Nissen, S.E., Wolski, K., Effect of rosiglitazone on the risk of myocardial infarction and death from cardiovascular causes (2007) N. Engl. J. Med., 356, pp. 2457-2471 Grey, A., Bolland, M., Gamble, G., Wattie, D., Horne, A., Davidson, J.A., Reid, I.R., The peroxisome proliferator-activated receptor-γ agonist rosiglitazone decreases bone formation and bone mineral density in healthy postmenopausal women. A randomized, controlled trial (2007) J. Clin. Endocrinol. Metab., 92, pp. 1305-1310 Morrison, R.F., Farmer, S.R., Hormonal signaling and transcriptional control of adipocyte differentiation (2000) J. Nutr., 130, pp. 3116S-3121S Tontonoz, P., Hu, E.A., Spiegelman, B.M., Stimulation of adipogenesis in fibroblasts by PPARγ2, a lipid-activated transcription factor (1994) Cell, 79, pp. 1147-1156 Willson, T.M., Lambert, M.H., Kliewer, S.A., Peroxisome proliferator-activated receptor γ and metabolic disease (2001) Annu. Rev. Biochem., 70, pp. 341-367 Nolte, R.T., Wisely, G.B., Westin, S., Cobb, J.E., Lambert, M.H., Kurokawa, R., Rosenfeld, M.G., Milburn, M.V., Ligand binding and co-activator assembly of the peroxisome proliferator-activated receptor-γ (1998) Nature, 395, pp. 137-143 Nagy, L.A., Schwabe, J.W., Mechanism of the nuclear receptor molecular switch (2004) Trends Biochem. Sci., 29, pp. 317-324 Choi, J.H., Banks, A.S., Estall, J.L., Kajimura, S., Boström, P., Laznik, D., Ruas, J.L., Spiegelman, B.M., Anti-diabetic drugs inhibit obesity-linked phosphorylation of PPARγ by Cdk5 (2010) Nature, 466, pp. 451-456 Da Costa Leite, L.F., Veras Mourão, R.H., De Lima Mdo, C., Galdino, S.L., Hernandes, M.Z., De Assis Rocha Neves, F., Vidal, S., Da Rocha Pitta, I., Synthesis, biological evaluation and molecular modeling studies of arylidene-thiazolidinediones with potential hypoglycemic and hypolipidemic activities (2007) Eur. J. Med. Chem., 42, pp. 1263-1271 Janderová, L., McNeil, M., Murrell, A.N., Mynatt, R.L., Smith, S.R., Human mesenchymal stem cells as an in vitro model for human adipogenesis (2003) Obes. Res., 11, pp. 65-74 Bonora, E., Moghetti, P., Zancanaro, C., Cigolini, M., Querena, M., Cacciatori, V., Corgnati, A.A., Muggeo, M., Estimates of in vivo insulin action in man. Comparison of insulin tolerance tests with euglycemic and hyperglycemic glucose clamp studies (1989) J. Clin. Endocrinol. Metab., 68, pp. 374-378 The CCP4 suite. Programs for protein crystallography (1994) Acta Crystallogr. D Biol. Crystallogr., 50, pp. 760-763. , Collaborative Computational Project, Number 4 McCoy, A.J., Grosse-Kunstleve, R.W., Adams, P.D., Winn, M.D., Storoni, L.C., Read, R.J., Phaser crystallographic software (2007) J. Appl. Crystallogr., 40, pp. 658-674 Adams, P.D., Afonine, P.V., Bunkóczi, G., Chen, V.B., Davis, I.W., Echols, N., Headd, J.J., Zwart, P.H., PHENIX. A comprehensive Python-based system for macromolecular structure solution (2010) Acta Crystallogr. D Biol. Crystallogr., 66, pp. 213-221 Emsley, P., Lohkamp, B., Scott, W.G., Cowtan, K., Features and development of Coot (2010) Acta Crystallogr. D Biol. Crystallogr., 66, pp. 486-501 Clauser, K.R., Baker, P.A., Burlingame, A.L., Role of accurate mass measurement (±10 ppm) in protein identification strategies employing MS or MS/MS and database searching (1999) Anal. Chem., 71, pp. 2871-2882 Figueira, A.C., Saidemberg, D.M., Souza, P.C., Martínez, L., Scanlan, T.S., Baxter, J.D., Skaf, M.S., Polikarpov, I., Analysis of agonist and antagonist effects on thyroid hormone receptor conformation by hydrogen/deuterium exchange (2011) Mol. Endocrinol., 25, pp. 15-31 Gampe Jr., R.T., Montana, V.G., Lambert, M.H., Miller, A.B., Bledsoe, R.K., Milburn, M.V., Kliewer, S.A., Xu, H.E., Asymmetry in the PPARγ/RXRα crystal structure reveals the molecular basis of heterodimerization among nuclear receptors (2000) Mol. Cell, 5, pp. 545-555 Martínez, L., Andreani, R., Martínez, J.M., Convergent algorithms for protein structural alignment (2007) BMC Bioinformatics, 8, p. 306 Gordon, J.C., Myers, J.B., Folta, T., Shoja, V., Heath, L.S., Onufriev, A., H++. A server for estimating pKas and adding missing hydrogens to macromolecules (2005) Nucleic Acids Res., 33, pp. W368-W371 Humphrey, W., Dalke, A.A., Schulten, K., VMD: Visual molecular dynamics (1996) J. Mol. Graph., 14, pp. 33-38+27-28 MacKerell, A.D., Bashford, D., Bellott, Dunbrack, R.L., Evanseck, J.D., Field, M.J., Fischer, S., Karplus, M., All-atom empirical potential for molecular modeling and dynamics studies of proteins (1998) J. Phys. Chem. B, 102, pp. 3586-3616 Jorgensen, W.L., Chandrasekhar, J., Madura, J.D., Impey, R.W.A., Klein, M.L., Comparison of simple potential functions for simulating liquid water (1983) J. Chem. Phys., 79, pp. 926-935 Hansson, A., Souza, P.C.T., Silveira, R.L., Martínez, L., Skaf, M.S., CHARMM force field parametrization of rosiglitazone (2011) Int. J. Quantum Chem., 111, pp. 1346-1354 Leach, A., (2001) Molecular Modeling: Principles and Applications, , 2nd Ed., Prentice Hall, Harlow, UK Ryckaert, J., Ciccotti, G.A., Berendsen, H., Numerical integration of the Cartesian equations of motion of a system with constraints. Molecular dynamics of n-alkanes (1977) J. Comput. Phys., 23, pp. 327-341 Phillips, J.C., Braun, R., Wang, W., Gumbart, J., Tajkhorshid, E., Villa, E., Chipot, C., Schulten, K., Scalable molecular dynamics with NAMD (2005) J. Comput. Chem., 26, pp. 1781-1802 Mourão, R.H., Silva, T.G., Soares, A.L., Vieira, E.S., Santos, J.N., Lima, M.C., Lima, V.L., Pitta, I.R., Synthesis and biological activity of novel acridinylidene and benzylidene thiazolidinediones (2005) Eur. J. Med. Chem., 40, pp. 1129-1133 Lu, M., Sarruf, D.A., Talukdar, S., Sharma, S., Li, P., Bandyopadhyay, G., Nalbandian, S., Olefsky, J.M., Brain PPAR-γ promotes obesity and is required for the insulin-sensitizing effect of thiazolidinediones (2011) Nat. Med., 17, pp. 618-622 Ryan, K.K., Li, B., Grayson, B.E., Matter, E.K., Woods, S.C., Seeley, R.J., A role for central nervous system PPAR-γ in the regulation of energy balance (2011) Nat. Med., 17, pp. 623-626 Zhang, H., Zhang, A., Kohan, D.E., Nelson, R.D., Gonzalez, F.J., Yang, T., Collecting duct-specific deletion of peroxisome proliferator-activated receptor γ blocks thiazolidinedione-induced fluid retention (2005) Proc. Natl. Acad. Sci. U.S.A., 102, pp. 9406-9411 Ohno, H., Shinoda, K., Spiegelman, B.M., Kajimura, S., PPARγ agonists induce a white-to-brown fat conversion through stabilization of PRDM16 protein (2012) Cell Metab., 15, pp. 395-404 Maier, C.S., Deinzer, M.L., Protein conformations, interactions, and H/D exchange (2005) Methods Enzymol., 402, pp. 312-360 Ali, A.A., Weinstein, R.S., Stewart, S.A., Parfitt, A.M., Manolagas, S.C., Jilka, R.L., Rosiglitazone causes bone loss in mice by suppressing osteoblast differentiation and bone formation (2005) Endocrinology, 146, pp. 1226-1235 Yaturu, S., Bryant, B.A., Jain, S.K., Thiazolidinedione treatment decreases bone mineral density in type 2 diabetic men (2007) Diabetes Care, 30, pp. 1574-1576 Schwartz, A.V., Sellmeyer, D.E., Vittinghoff, E., Palermo, L., Lecka-Czernik, B., Feingold, K.R., Strotmeyer, E.S., Cummings, S.R., Thiazolidinedione use and bone loss in older diabetic adults (2006) J. Clin. Endocrinol. Metab., 91, pp. 3349-3354 Olefsky, J.M., Treatment of insulin resistance with peroxisome proliferator-activated receptor γ agonists (2000) J. Clin. Invest., 106, pp. 467-472 Choi, J.H., Banks, A.S., Kamenecka, T.M., Busby, S.A., Chalmers, M.J., Kumar, N., Kuruvilla, D.S., Griffin, P.R., Antidiabetic actions of a non-agonist PPARγ ligand blocking Cdk5-mediated phosphorylation (2011) Nature, 477, pp. 477-481 Trujillo, M.E., Scherer, P.E., Adipose tissue-derived factors. Impact on health and disease (2006) Endocr. Rev., 27, pp. 762-778 Chandra, V., Huang, P., Hamuro, Y., Raghuram, S., Wang, Y., Burris, T.P., Rastinejad, F., Structure of the intact PPAR-γ-RXR-nuclear receptor complex on DNA (2008) Nature, 456, pp. 350-356 Burgermeister, E., A novel partial agonist of peroxisome proliferator-activated receptor-γ (PPARγ) recruits PPARγ-coactivator-1α, prevents triglyceride accumulation, and potentiates insulin signaling in vitro (2006) Molecular Endocrinology, 20, pp. 809-830 Bruning, J.B., Chalmers, M.J., Prasad, S., Busby, S.A., Kamenecka, T.M., He, Y., Nettles, K.W., Griffin, P.R., Partial agonists activate PPARγ using a helix 12-independent mechanism (2007) Structure, 15, pp. 1258-1271 Acton III, J.J., Black, R.M., Jones, A.B., Moller, D.E., Colwell, L., Doebber, T.W., Macnaul, K.L., Wood, H.B., Benzoyl 2-methyl indoles as selective PPARγ modulators (2005) Bioorg. Med. Chem. Lett., 15, pp. 357-362 Kim, J.Y., Van De Wall, E., Laplante, M., Azzara, A., Trujillo, M.E., Hofmann, S.M., Schraw, T., Scherer, P.E., Obesity-associated improvements in metabolic profile through expansion of adipose tissue (2007) J. Clin. Invest., 117, pp. 2621-2637