Dana S. Kuruvilla

TL;DR: Novel synthetic compounds are described that have a unique mode of binding to PPARγ, completely lack classical transcriptional agonism and block the Cdk5-mediated phosphorylation in cultured adipocytes and in insulin-resistant mice, and one such compound, SR1664, has potent antidiabetic activity while not causing the fluid retention and weight gain that are serious side effects of many of the PParγ drugs.

TL;DR: It is revealed that synthetic PPARγ ligands also bind to an alternate site, leading to unique receptor conformational changes that impact coregulator binding, transactivation and target gene expression, and is neither blocked by covalently bound synthetic antagonists nor by endogenous ligands indicating non-overlapping binding with the canonical pocket.

TL;DR: It is reported that peroxisome proliferator-activated receptor γ (PPARγ) modulators can sample multiple binding modes manifesting in multiple receptor conformations in slow conformational exchange and that ligand and receptor dynamics affect the graded transcriptional output of PPARγ modulators.

TL;DR: The structural mechanism by which SR1664 actively antagonizes PPARγ is identified, and findings are extended to develop the inverse agonist SR2595, which promotes induction of osteogenic differentiation and suggests a therapeutic approach to promote bone formation.

TL;DR: Results suggest that pharmacological repression of RORγ may represent a strategy for treatment of obesity by increasing thermogenesis and fatty acid oxidation, while inhibition of hormone-sensitive lipase activity results in a reduction of serum free fatty acids, leading to improved peripheral insulin sensitivity.