Premium
Modulation of PPARγ activity with pharmaceutical agents: Treatment of insulin resistance and atherosclerosis
Author(s) -
Wang Minghan,
Tafuri Sherrie
Publication year - 2003
Publication title -
journal of cellular biochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.028
H-Index - 165
eISSN - 1097-4644
pISSN - 0730-2312
DOI - 10.1002/jcb.10492
Subject(s) - adipogenesis , peroxisome proliferator activated receptor , insulin resistance , nuclear receptor , receptor , selective estrogen receptor modulator , in vivo , ppar agonist , chemistry , insulin , lipid metabolism , medicine , pharmacology , endocrinology , microbiology and biotechnology , biology , adipose tissue , estrogen receptor , transcription factor , biochemistry , gene , cancer , breast cancer
Abstract The anti‐diabetic thiazolidinediones (TZDs) are a class of compounds with insulin‐sensitizing activity that were originally discovered using in vivo pharmacological screens. In subsequent binding studies, TZDs were demonstrated to enhance insulin action by activating peroxisome proliferator‐activated receptor gamma (PPARγ). PPARγ is a member of the ligand‐activated nuclear receptor superfamily that promotes adipogenesis and enhances insulin sensitivity by controlling the expression of genes in glucose and lipid metabolism. Given the large size of the ligand binding pocket in PPARγ, novel classes of both full and partial agonists that are structurally distinct from TZDs have been discovered. These compounds have been effective tools in differentiating adipogenic and insulin‐sensitizing activities as well as tissue selectivity of PPARγ activation. This information has led to the hypothesis that one ligand can activate or inactivate PPARs depending upon the tissue in which the PPAR resides. Thus particular compounds can be designated selective PPAR modulators or SPPARMs, a concept similar to that observed with the activation of estrogen receptor (ER) by SERMS. Additionally, both preclinical and clinical data suggest that PPARγ activation is useful for the prevention of atherosclerosis. However, the effects of TZDs on plasma lipid profiles do not solely account for their anti‐atherogenic effects. Recent studies with macrophage cells and animal models for atherosclerosis indicate that TZDs reduce the size and number of lesions formed in the vessel wall by modulating foam cell formation and inflammatory responses by macrophages. Thus in addition to the treatment of type II diabetes, PPARγ agonists can be potentially employed for the treatment of atherosclerosis in general population. J. Cell. Biochem. 89: 38–47, 2003. © 2003 Wiley‐Liss, Inc.