Selective peroxisome proliferator-activated receptor γ (PPARγ) modulation as a strategy for safer therapeutic PPARγ activation

Abstract

Peroxisome proliferator-activated receptor gamma (PPARgamma) is a clinically validated target for treatment of insulin resistance. PPARgamma activation by full agonists such as thiazolidinediones has shown potent and durable glucose-lowering activity in patients with type 2 diabetes without the concern for hypoglycemia or gastrointestinal toxicities associated with some other medications used to treat this disease. However, thiazolidinediones are linked to safety and tolerability issues such as weight gain, fluid retention, edema, congestive heart failure, and bone fracture. Distinctive properties of PPARgamma provide the opportunity for selective modulation of the receptor such that desirable therapeutic effects may be attained without the unwanted effects of full activation. PPARgamma is a nuclear receptor that forms a complex with coreceptor RXR and a cell type- and cell state-specific array of coregulators to control gene transcription. PPARgamma affinity for these components, and hence transcriptional response, is determined by the conformational changes induced by ligand binding within a complex pocket with multiple interaction points. This molecular mechanism thereby offers the opportunity for selective modulation. A desirable selective PPARgamma modulator profile would include high-affinity interaction with the PPARgamma-binding pocket in a manner that leads to retention of the insulin-sensitizing activity that is characteristic of full agonists as well as mitigation of the effects leading to increased adiposity, fluid retention, congestive heart failure, and bone fracture. Examples of endogenous and synthetic selective PPARgamma modulator (SPPARM) ligands have been identified. SPPARM drug candidates are being tested clinically and provide support for this strategy.

C333H Ameliorated Insulin Resistance through Selectively Modulating Peroxisome Proliferator-Activated Receptor γ in Brown Adipose Tissue of db/db Mice

“…Importantly, SPPARMs also selectively regulate PPARγ target gene transcription in response to specific cofactor recruitment. [18][19][20] In present report, the insulin sensitizing properties of C333h were further confirmed in diabetic db/db mice and insulin resistant obese MSG rats. In db/db mice, C333H was at least as effective as the full PPARγ agonist rosiglitazone in ameliorating the glucose intolerance and increasing ISI.…”

Can a Selective PPARγ Modulator Improve Glycemic Control in Patients With Type 2 Diabetes With Fewer Side Effects Compared With Pioglitazone?

“…Insulin-stimulated phosphatidylinositol 3-kinase activity in skeletal muscle and adipose tissue of DIO mice was significantly reduced by ;50-65%, but this was restored completely by INT131 therapy. Concurrently, insulinmediated Akt phosphorylation also increased after INT131 treatment in DIO mice (11). Thus, preclinical studies suggest that INT131 normalizes obesity-related defects in insulin signaling and action in insulin target tissues without stimulating preadipocyte stimulation or lipid accumulation.…”

“…INT131 does not stimulate rodent or human preadipocytes to differentiate or accumulate lipid (12) and has equal or greater efficacy to stimulate adiponectin, a marker of PPARg activation, in rodents and healthy subjects (10,24). With use of the DIO mouse model of obesity and insulin resistance, treatment with INT131 enhanced systemic insulin sensitivity independent from changes in adiposity (11). Insulin-stimulated phosphatidylinositol 3-kinase activity in skeletal muscle and adipose tissue of DIO mice was significantly reduced by ;50-65%, but this was restored completely by INT131 therapy.…”

“…INT131 besylate is a selective PPARg modulator (SPPARM) (10,11). Chemically, INT131 is structurally distinct from the TZDs and represents a new class of non-TZD PPARg ligands (12).…”

The antiproliferative and proapoptotic effects of cladosporols A and B are related to their different binding mode as PPARγ ligands

“…Multiple PPARc coactivators have been identified so far, but it seems unlikely that each coactivator may regulate a single pathway; more conceivably, diverse coregulators cooperate to activate gene transcription. The identification of SPPARMs implies a different affinity for the ligand-bound receptor to achieve partial or full activation [20,58]. This differential result could be due to the conformational changes of the PPARc LBD induced by ligands unveiling a dynamic response of the receptor.…”