Selective peroxisome proliferator-activated receptor γ (PPARγ) modulation as a strategy for safer therapeutic PPARγ activation123

• Published in: The American journal of clinical nutrition 2010-01, Vol.91 (1), p.267S-270S
• Main Authors: Higgins, Linda Slanec, DePaoli, Alex M
• Format: Article
• Language: English
• ISSN: 0002-9165; 1938-3207
• DOI: 10.3945/ajcn.2009.28449E

Peroxisome proliferator-activated receptor γ (PPARγ) is a clinically validated target for treatment of insulin resistance. PPARγ 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 PPARγ provide the opportunity for selective modulation of the receptor such that desirable therapeutic effects may be attained without the unwanted effects of full activation. PPARγ 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. PPARγ 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 PPARγ modulator profile would include high-affinity interaction with the PPARγ-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 PPARγ modulator (SPPARM) ligands have been identified. SPPARM drug candidates are being tested clinically and provide support for this strategy. Am J Clin Nutr 2010;91 (suppl):267S–72S.