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

Abstract

Peroxisome proliferator-activated receptor γ (PPARγ) is a unique target for insulin sensitizer agents. These drugs have been used for the clinical treatment of type 2 diabetes for almost twenty years. However, serious safety issues are associated with the PPARγ agonist thiazolidinediones (TZDs). Selective PPARγ modulators (SPPARMs) which retain insulin sensitization without TZDs-like side effects are emerging as a promising new generation of insulin sensitizers. C333H is a novel structure compound synthesized by our laboratory. In diabetic rodent models, C333H has insulin-sensitizing and glucose-lowering activity comparable to that of TZDs, and causes no significant increase in body weight or adipose tissue weight in db/db mice. In diabetic db/db mice, C333H elevated circulating high molecular weight adiponectin isoforms, decreased PPARγ 273 serine phosphorylation in brown adipose tissue and selectively modulated the expression of a subset of PPARγ target genes in adipose tissue. In vitro, C333H weakly recruited coactivator and weakly dissociated corepressor activity. These findings suggest that C333H has similar properties to SPPARMs and may be a potential therapeutic agent for the treatment of type 2 diabetes.Key words C333H; peroxisome proliferator-activated receptor γ (PPAR γ); insulin resistance; selective PPARγ modulator; type 2 diabetes Thiazolidinediones (TZDs) are unique insulin sensitizing drugs used for the treatment of type 2 diabetes and other metabolic syndromes associated with insulin resistance. 1)The γ subtype of peroxisome proliferator activated receptors (PPARγ) acts as target for TZDs and is key regulator of glucose homeostasis and adipocyte differentiation. As a nuclear receptor, PPARγ firstly interacts with retinoid X receptor α (RXRα) to form a heterodimer, which in turn recruits specific coactivators or corepressors depending on physiological environment. It then binds to specific response elements (PPREs) within promoter region of target genes to control gene transcription.2) However, the unwanted effects of TZDs including body weight gain, edema, increased risks of congestive heart failure, and increased rate of bone fracture restrict the clinical usage of these drugs.It has been known for several years that the insulin sensitizing effects can be obtained by PPARγ ligands without the risk of TZDs-like side effects. Genetic and epidemic studies have shown that the side effects of TZDs are closely related to overactivation of PPARγ, whereas physiologically appropriate PPARγ activity is beneficial in terms of reducing insulin resistance and other risks associated with type 2 diabetes. 3-5)More recently, it has been reported that the inhibition of CDK5 mediated PPARγ 273 serine phosphorylation, rather than PPARγ agonism and lipogenic effects, constitutes the key target for insulin sensitization and the antidiabetic effects of PPARγ agonists.6) The same workers reported that a nonagonist PPARγ ligand, SR1664, inhibited PPARγ 273 serine phosphorylation, and enhanced insulin sensitivity withou...

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