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A Novel Partial Agonist of Peroxisome Proliferator-Activated Receptor- (PPAR) Recruits PPAR-Coactivator-1, Prevents Triglyceride Accumulation, and Potentiates Insulin Signaling in Vitro

Department of Vascular and Metabolic Diseases (E.B., A.S., A.F., J.M., E.S., E.N.), Department of Discovery Chemistry (J.B., M.S., B.G., A.R., A.R., B.K., H.P.M.), and Department of Exploratory Development (M.M.), Pharmaceuticals Division, Fa. Hoffmann-La Roche AG, CH-4070 Basel, Switzerland

Address all correspondence and requests for reprints to: Dr. Markus Meyer, Fa. Hoffmann-La Roche AG, Pharmaceuticals Division, Department of Exploratory Development (PDME), Building 15, Room 1.042A, Grenzacherstrasse 124, CH-4070 Basel, Switzerland. E-mail: markus.meyer{at}roche.com.

Partial agonists of peroxisome proliferator-activated receptor- (PPAR), also termed selective PPAR modulators, are expected to uncouple insulin sensitization from triglyceride (TG) storage in patients with type 2 diabetes mellitus. These agents shall thus avoid adverse effects, such as body weight gain, exerted by full agonists such as thiazolidinediones. In this context, we describe the identification and characterization of the isoquinoline derivative PA-082, a prototype of a novel class of non-thiazolidinedione partial PPAR ligands. In a cocrystal with PPAR 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-coactivator-1 (PGC1) to the receptor, a feature shared with other selective PPAR modulators. 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 wild-type PGC1 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 cross-talk of TNF on protein kinase B (AKT) phosphorylation in mature adipocytes and HepG2 human hepatoma cells. PGC1 is a key regulator of energy expenditure and down-regulated in diabetics. We thus propose that selective recruitment of PGC1 to favorable PPAR-target genes provides a possible molecular mechanism whereby partial PPAR agonists dissociate TG accumulation from insulin signaling.

NURSA Molecule Pages Link:

Nuclear Receptors:   PPARγ  |  ERRα

Coregulators:   PGC-1  |  SRC-1  |  GRIP1  |  AIB1  |  NCOR

Ligands:   GW 9662  |  Dexamethasone  |  Rosiglitazone

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