+ Site Statistics
+ Search Articles
+ PDF Full Text Service
How our service works
Request PDF Full Text
+ Follow Us
Follow on Facebook
Follow on Twitter
Follow on LinkedIn
+ Subscribe to Site Feeds
Most Shared
PDF Full Text
+ Translate
+ Recently Requested

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



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



American Journal of Clinical Nutrition 91(1): 267s-272s



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.

Please choose payment method:






(PDF emailed within 0-6 h: $19.90)

Accession: 055696202

Download citation: RISBibTeXText

PMID: 19906796

DOI: 10.3945/ajcn.2009.28449e


Related references

Selective peroxisome proliferator-activated receptor gamma modulation as a strategy for safer therapeutic PPAR gamma activation. American Journal Of Clinical Nutrition: 1, Supplement, 267s-272s, 2010

Activation of human T lymphocytes is inhibited by peroxisome proliferator-activated receptor gamma (PPARgamma) agonists. PPARgamma co-association with transcription factor NFAT. Journal of Biological Chemistry 275(7): 4541-4544, 2000

Transactivation by retinoid X receptor-peroxisome proliferator-activated receptor gamma (PPARgamma) heterodimers: intermolecular synergy requires only the PPARgamma hormone-dependent activation function. Molecular and Cellular Biology 18(6): 3483-3494, 1998

Novel Transcriptome Profiling Analyses Demonstrate that Selective Peroxisome Proliferator-Activated Receptor gamma PPARgamma Modulators Display Attenuated and Selective Gene Regulatory Activity in Comparison with PPARgamma Full Agonists. 2012

Macrophages in human atheroma contain PPARgamma: differentiation-dependent peroxisomal proliferator-activated receptor gamma(PPARgamma) expression and reduction of MMP-9 activity through PPARgamma activation in mononuclear phagocytes in vitro. American Journal of Pathology 153(1): 17-23, 1998

A peroxisome proliferator-activated receptor gamma (PPARgamma)/PPARgamma coactivator 1beta autoregulatory loop in adipocyte mitochondrial function. Journal of Biological Chemistry 286(35): 30723-30731, 2011

The mechanisms by which both heterozygous peroxisome proliferator-activated receptor gamma (PPARgamma) deficiency and PPARgamma agonist improve insulin resistance. Journal of Biological Chemistry 276(44): 41245-41254, 2001

The insulin receptor: a new anticancer target for peroxisome proliferator-activated receptor-gamma (PPARgamma) and thiazolidinedione-PPARgamma agonists. Endocrine-Related Cancer 15(1): 325-335, 2008

Expression of peroxisome-proliferator activated receptor-gamma (PPARgamma) and the PPARgamma co-activator, PGC-1, in human breast cancer correlates with clinical outcomes. International Journal of Cancer 106(5): 752-757, 2003

Transcriptional coactivator PRIP, the peroxisome proliferator-activated receptor gamma (PPARgamma)-interacting protein, is required for PPARgamma-mediated adipogenesis. Journal of Biological Chemistry 278(28): 25281-4, 2003

A dominant-negative peroxisome proliferator-activated receptor gamma (PPARgamma) mutant is a constitutive repressor and inhibits PPARgamma-mediated adipogenesis. Journal of Biological Chemistry 275(8): 5754-5759, 2000

Stimulation of adipogenesis, peroxisome proliferator-activated receptor-gamma (PPARgamma), and thyrotropin receptor by PPARgamma agonist in human orbital preadipocyte fibroblasts. Journal of Clinical Endocrinology and Metabolism 87(5): 2352-2358, 2002

HER2 regulation of peroxisome proliferator-activated receptor gamma (PPARgamma) expression and sensitivity of breast cancer cells to PPARgamma ligand therapy. Clinical Cancer Research 9(8): 3198-3203, 2003

The effect of activation of peroxisome proliferator-activated receptor gamma (PPARgamma) on human monocyte function: PPARgamma ligands do not inhibit tumor necrosis factor-alpha release in human monocytic cell line THP-1. Cell Biology and Toxicology 16(2): 131-135, 2000

Albumin regulates induction of peroxisome proliferator-activated receptor-gamma (PPARgamma) by 15-deoxy-delta(12-14)-prostaglandin J(2) in vitro and may be an important regulator of PPARgamma function in vivo. Endocrinology 142(2): 551-556, 2001