help button home button Endocrine Society Molecular Endocrinology
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH
This version published online on December 22, 2005
Molecular Endocrinology, doi:10.1210/me.2005-0171
A more recent version of this article appeared on April 1, 2006
This Article
Right arrow Author Manuscript (PDF)
Right arrow All Versions of this Article:
20/4/809    most recent
Author Manuscript (PDF)
Right arrow Purchase Article
Right arrow View Shopping Cart
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow NURSA Molecule Pages Link
Right arrow Request Copyright Permission
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Burgermeister, E.
Right arrow Articles by Meyer, M.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Burgermeister, E.
Right arrow Articles by Meyer, M.
Right arrowPubmed/NCBI databases
*Protein*Structure
*Compound via MeSH
*Substance via MeSH
Hazardous Substances DB
*GLUCOSE

Submitted on April 26, 2005
Accepted on December 13, 2005

A novel partial agonist of peroxisome proliferator-activated receptor-gamma (PPAR{gamma}) recruits PPAR{gamma}-coactivator-1 alpha (PGC1{alpha}), prevents triglyceride accumulation and potentiates insulin signaling in vitro

Elke Burgermeister*, Astride Schnoebelen, Angele Flament, Jörg Benz, Martine Stihle, Bernard Gsell, Arne Rufer, Armin Ruf, Bernd Kuhn, Hans Peter Märki, Jacques Mizrahi, Elena Sebokova, Eric Niesor, and Markus Meyer

Department of Vascular & Metabolic Diseases, Department of Discovery Chemistry, Department of Exploratory Development, Pharmaceuticals Division, Fa. Hoffmann-La Roche AG, Grenzacher Strasse 124, CH-4070 Basel, Switzerland

* To whom correspondence should be addressed. E-mail: elke.burgermeister{at}roche.com.

Partial agonists of peroxisome proliferator-activated receptor-gamma (PPAR{gamma}), also termed selective PPAR{gamma} modulators (SPPAR{gamma}Ms), are expected to uncouple insulin sensitization from triglyceride (TG) storage in patients with type II diabetes mellitus. These agents shall thus avoid adverse effects, such as body weight gain, exerted by full agonists like thiazolidinediones (TZD). In this context, we describe the identification and characterization of the isoquinoline derivative PA-082, a prototype of a novel class of non-TZD partial PPAR{gamma}-ligands. In a cocrystal with PPAR{gamma} it was bound within the ligand-binding pocket without direct contact to helix 12. The compound displayed partial agonism in biochemical and cell-based transactivation assays and caused preferential recruitment of PPAR{gamma}-coactivator-1 alpha (PGC1{alpha}) to the receptor, a feature shared with other SPPAR{gamma}Ms. It antagonized rosiglitazone-driven transactivation and TG accumulation during de novo adipogenic differentiation of murine C3H10T1/2 mesenchymal stem cells. The latter effect was mimicked by overexpression of wildtype PGC1{alpha} but not its LXXLL-deficient mutant. Despite failing to promote TG loading, PA-082 induced mRNAs of genes encoding components of insulin signaling and adipogenic differentiation pathways. It potentiated glucose uptake and inhibited the negative crosstalk of TNF{alpha} on protein kinase B (AKT) phosphorylation in mature adipocytes and HepG2 human hepatoma cells. PGC1{alpha} is a key regulator of energy expenditure and down-regulated in diabetics. We thus propose that selective recruitment of PGC1{alpha} to favorable PPAR{gamma}-target genes provides a possible molecular mechanism how partial PPAR{gamma}-agonists dissociate TG accumulation from insulin signaling.
Key words: PPAR • peroxisome proliferator-activated receptor gamma • peroxisome proliferator-activated receptor gamma coactivator-1 alpha • triglyceride accumulation • insulin signaling • crystal structure • isoquinoline

NURSA Molecule Pages Link:

Nuclear Receptors:   PPARγ  |  ERRα
Coregulators:   PGC-1  |  SRC-1  |  GRIP1  |  AIB1  |  NCOR
Ligands:   GW 9662  |  Dexamethasone  |  Rosiglitazone



This article has been cited by other articles:


Home page
 Mol. Pharmacol.Home page
M. Einstein, T. E. Akiyama, G. A. Castriota, C. F. Wang, B. McKeever, R. T. Mosley, J. W. Becker, D. E. Moller, P. T. Meinke, H. B. Wood, et al.
The Differential Interactions of Peroxisome Proliferator-Activated Receptor {gamma} Ligands with Tyr473 Is a Physical Basis for Their Unique Biological Activities
Mol. Pharmacol., January 1, 2008; 73(1): 62 - 74.
[Abstract] [Full Text] [PDF]

Home page
 Cancer Res.Home page
E. Burgermeister, X. Xing, C. Rocken, M. Juhasz, J. Chen, M. Hiber, K. Mair, M. Shatz, M. Liscovitch, R. M. Schmid, et al.
Differential Expression and Function of Caveolin-1 in Human Gastric Cancer Progression
Cancer Res., September 15, 2007; 67(18): 8519 - 8526.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
J. N. Feige, L. Gelman, D. Rossi, V. Zoete, R. Metivier, C. Tudor, S. I. Anghel, A. Grosdidier, C. Lathion, Y. Engelborghs, et al.
The Endocrine Disruptor Monoethyl-hexyl-phthalate Is a Selective Peroxisome Proliferator-activated Receptor {gamma} Modulator That Promotes Adipogenesis
J. Biol. Chem., June 29, 2007; 282(26): 19152 - 19166.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
A. L. B. Ambrosio, S. M. G. Dias, I. Polikarpov, R. B. Zurier, S. H. Burstein, and R. C. Garratt
Ajulemic Acid, a Synthetic Nonpsychoactive Cannabinoid Acid, Bound to the Ligand Binding Domain of the Human Peroxisome Proliferator-activated Receptor {gamma}
J. Biol. Chem., June 22, 2007; 282(25): 18625 - 18633.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
G. Pochetti, C. Godio, N. Mitro, D. Caruso, A. Galmozzi, S. Scurati, F. Loiodice, G. Fracchiolla, P. Tortorella, A. Laghezza, et al.
Insights into the Mechanism of Partial Agonism: CRYSTAL STRUCTURES OF THE PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR {gamma} LIGAND-BINDING DOMAIN IN THE COMPLEX WITH TWO ENANTIOMERIC LIGANDS
J. Biol. Chem., June 8, 2007; 282(23): 17314 - 17324.
[Abstract] [Full Text] [PDF]

Home page
 Exp. Biol. Med.Home page
A. Klopotek, F. Hirche, and K. Eder
PPAR{gamma} Ligand Troglitazone Lowers Cholesterol Synthesis in HepG2 and Caco-2 Cells via a Reduced Concentration of Nuclear SREBP-2
Experimental Biology and Medicine, September 1, 2006; 231(8): 1365 - 1372.
[Abstract] [Full Text] [PDF]


HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH
Endocrinology Endocrine Reviews J. Clin. End. & Metab.
Molecular Endocrinology Recent Prog. Horm. Res. All Endocrine Journals
Copyright © 2005 by The Endocrine Society