GQ-16, a Novel Peroxisome Proliferator-activated Receptor gamma (PPAR gamma) Ligand, Promotes Insulin Sensitization without Weight Gain

Autor(es):Mostrar menos -

Amato, Angelica A. ^[1] ; Rajagopalan, Senapathy ^[2] ; Lin, Jean Z. ^[3] ; Carvalho, Bruno M. ^[4] ; Figueira, Ana C. M. ^[5] ; Lu, Jenny ^[2] ; Ayers, Stephen D. ^[2] ; Mottin, Melina ^[6] ; Silveira, Rodrigo L. ^[6] ; Souza, Paulo C. T. ^[6] ; Mourao, Rosa H. V. ^[7] ; Saad, Mario J. A. ^[4] ; Togashi, Marie ^[1] ; Simeoni, Luiz A. ^[1] ; Abdalla, Dulcineia S. P. ^[8] ; Skaf, Munir S. ^[6] ; Polikparpov, Igor ^{[9, 10]} ; Lima, Maria C. A. ^[11] ; Galdino, Suely L. ^[11] ; Brennan, Richard G. ^[12] ; Baxter, John D. ^[2] ; Pitta, Ivan R. ^[11] ; Webb, Paul ^[2] ; Phillips, Kevin J. ^[2] ; Neves, Francisco A. R. ^[1]

Afiliação do(s) autor(es):Mostrar menos -

^[1] Univ Brasilia, Lab Farmacol Mol, Dept Ciencias Farmaceut, Fac Ciencias Saude, BR-70919970 Brasilia, DF - Brazil

^[2] Methodist Hosp, Res Inst, Diabet Res Ctr, Houston, TX 77030 - USA

^[3] Univ Houston, Dept Biol & Biochem, Ctr Nucl Receptors & Cell Signaling, Houston, TX 77204 - USA

^[4] Univ Estadual Campinas, Dept Med Interna, BR-13083887 Sao Paulo - Brazil

^[5] Brazilian Assoc Synchrotron Light Technol, Natl Inst Biosci, BR-13083970 Sao Paulo - Brazil

^[6] Univ Estadual Campinas, Inst Chem, BR-13084862 Sao Paulo - Brazil

^[7] Univ Fed Oeste Para, Lab Bioprospeccao & Biol Expt, BR-68040070 Santarem, Para - Brazil

^[8] Univ Sao Paulo, Fac Ciencias Farmaceut, Dept Anal Clin & Toxicol, BR-05508900 Sao Paulo - Brazil

^[9] Univ Sao Paulo, BR-13560970 Sao Carlos, SP - Brazil

^[10] Inst Fis Sao Carlos, Dept Fis, BR-13560970 Sao Carlos, SP - Brazil

^[11] Univ Fed Pernambuco, Dept Antibiot, BR-50670901 Recife, PE - Brazil

^[12] Duke Univ, Sch Med, Dept Biochem, Durham, NC 27710 - USA

• Tipo de documento: Artigo Científico
• Fonte: Journal of Biological Chemistry; v. 287, n. 33, p. 28169-28179, AUG 10 2012.
• Citações Web of Science: 53

Resumo

The recent discovery that peroxisome proliferator-activated receptor gamma (PPAR gamma) 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 PPAR gamma activation. Further characterization of this compound shows GQ-16 to be an effective inhibitor of Cdk5-mediated phosphorylation of PPAR gamma. The structure of GQ-16 bound to PPAR gamma demonstrates that the compound utilizes a binding mode distinct from other reported PPAR gamma 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 beta-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{''} PPAR gamma-based therapeutics stabilize the beta-sheet/Ser-273 region and inhibit Cdk5-mediated phosphorylation while minimally invoking adipogenesis and classical agonism, is indeed a valid framework to develop improved PPAR gamma modulators that retain antidiabetic actions while minimizing untoward effects. (AU)

• Processo FAPESP: 10/08680-2 - Aspectos moleculares da degradação de biomassa lignocelulósica: dinâmica de enzimas e nanoarquitetura de paredes celulares de plantas
• Beneficiário: Rodrigo Leandro Silveira
• Modalidade de apoio: Bolsas no Brasil - Doutorado
• Processo FAPESP: 09/14108-2 - Simulações de dinâmica molecular de receptores nucleares: estimativas de energia livre ligante-proteína
• Beneficiário: Paulo Cesar Telles de Souza
• Modalidade de apoio: Bolsas no Brasil - Doutorado
• Processo FAPESP: 10/17048-8 - Regulação da transativação e transrepressão gênica mediada por receptores nucleares
• Beneficiário: Ana Carolina Migliorini Figueira
• Modalidade de apoio: Auxílio à Pesquisa - Regular