A Potent Antidiabetic Thiazolidinedione with Unique Peroxisome Proliferator-activated Receptor γ-activating Properties

Abstract

Thiazolidinediones (TZDs) constitute an exciting new class of antidiabetic compounds, which function as activating ligands for peroxisome proliferator-activated receptor ␥ (PPAR␥). Until now, there has been an excellent correlation between in vivo hypoglycemic potency and in vitro binding and activation of PPAR␥ by TZDs. We have characterized MCC-555, a novel thiazolidinedione ligand for PPAR␥ with unique functional properties. The antidiabetic potency of this compound is greater than that of other TZDs, including BRL49653, yet its binding affinity for PPAR␥ is less than 1 ⁄10 that of BRL49653. The effect of MCC-555 binding on PPAR␥ transcriptional activity is highly context-specific such that it can function as a full agonist, partial agonist, or antagonist depending on the cell type or DNA binding site. These transcriptional properties are partly explained by unique partial agonism of coactivator recruitment to PPAR␥. The properties of MCC-555 are mechanistically distinct from those of the estrogen receptor partial agonist and antagonist tamoxifen because the N terminus of PPAR␥ is not required for activation by MCC-555, and MCC-555 does not stimulate corepressor recruitment to PPAR␥. The context selectivity of MCC-555 may contribute to its enhanced hypoglycemic potency in vivo despite reduced affinity for PPAR␥ relative to other TZDs. Nuclear hormone receptors (NHRs)1 constitute a class of transcription factors with activity that is regulated by natural or synthetic lipophilic ligands (1). A number of NHRs are involved in developmental and/or metabolic processes, and modulation of NHR activity is an effective strategy in the treatment of a variety of cancers, such as breast cancer (2), prostate cancer (3), and acute promyleocytic leukemia (4), as well as metabolic diseases including thyroid disease (5) and diabetes. Non-insulin-dependent diabetes mellitus is a major cause of morbidity and mortality in industrialized nations and is characterized by a post-insulin receptor defect that has been difficult to target therapeutically until the recent discovery that thiazolidinediones (TZDs) enhance the actions of insulin at a level distal to the insulin receptor (6).The mechanism of TZD action is not completely understood, but a number of lines of evidence point to their function as ligands for a member of the NHR superfamily called peroxisome proliferator-activated receptor ␥ (PPAR␥), the natural ligand of which may be derived from or related to prostaglandin J2 (7-9). One of the most potent TZDs, BRL49653, binds to PPAR␥ with an affinity in the nanomolar range (10), and the rank order of TZD potency for in vivo plasma glucose lowering correlates well with their rank order potency for PPAR␥ activation (11, 12). Nevertheless, a number of questions remain with regard to the mechanism of TZD potentiation of insulin action. The main problem is that PPAR␥ is primarily expressed in adipose tissue (13, 14), whereas muscle is ordinarily the main site of insulin-dependent glucose disposal in mammals. This apparent paradox h...

Identification of Telmisartan as a Unique Angiotensin II Receptor Antagonist With Selective PPARγ–Modulating Activity

“…In fact, intense interest exists in the development of selective PPAR␥ modulators that can exert beneficial effects on the expression of genes that regulate carbohydrate and lipid metabolism without causing changes in gene expression that promote weight gain, fluid retention, or the other adverse effects associated with administration of conventional PPAR␥ activators. 29,40,43,50 In the current study, it is noteworthy that telmisartan attenuated weight gain despite the use of a pair-feeding protocol that ensured comparable food intakes among all of the experimental groups. Other partial agonists of PPAR␥ have also been shown to attenuate the weight gain ordinarily induced by a high-fat diet.…”

“…The relatively modest effect of telmisartan on adipogenesis is not surprising, given that other partial agonists of PPAR␥ have also been found to be relatively weak stimulators, or even inhibitors, of adipogenesis compared with full agonists such as rosiglitazone. 29,40,43 …”

Adipose Tissue Resistin Expression Is Severely Suppressed in Obesity and Stimulated by Peroxisome Proliferator-activated Receptor γ Agonists

“…Rosiglitazone and GW1929 are full PPAR␥ agonists (8,11). MCC-555 profiles as a low affinity full PPAR␥ agonist in cell-based assays but acts as a potent antidiabetic agent in vivo (12). Treatment with rosiglitazone, GW1929, or MCC-555 resulted in 50, 50, and 30% reductions in serum glucose levels, respectively, relative to treatment with vehicle alone and significant increases in insulin sensitivity (data not shown).…”

Antineoplastic effects of rosiglitazone and PPARγ transactivation in neuroblastoma cells

“…Thiazolidinediones (TZDs) are a class of molecules, which activate the nuclear receptor peroxisome proliferator-activated receptor g (PPARg) (Desvergne and Wahli, 1999) and promote association with the 9-cis retinoic X receptor (RXR) to form functional heterodimers that recognise its cognate DNA response element within target genes (Jude-Aubry et al, 1997; Reginato et al, 1998). In addition to their well-known effects on glucose homeostasis (Yki-Järvinen, 2004), TZDs have been shown to have antiinflammatory (Jiang et al, 1998, Marx et al, 2000 and antineoplastic effects (Koeffler, 2003, Grommes et al, 2004.…”