A novel peroxisome proliferator-activated receptor gamma ligand improves insulin sensitivity and promotes browning of white adipose tissue in obese mice

Evidence from laboratory and animal studies provides groundwork for understanding mechanisms and potential before human studies continue.

• Level A · Stronger Clinical Evidence
• Level B · Emerging clinical evidence with positive signals
• Level C · Early human research exploring benefits
• Level D · Scientific groundwork from lab and animal studies
• Emerging · Emerging topic under active research

Abstract (original English)

Objective Nuclear receptor Peroxisome Proliferator-Activated Receptor γ (PPARγ) is a promising target for the treatment of type 2 diabetes. The antidiabetic drug thiazolidinediones (TZDs) are potent insulin sensitizers as full agonists of PPARγ, but cause unwanted side effects. Recent discoveries have shown that TZDs improve insulin sensitivity by blocking PPARγ phosphorylation at S273, which decouples the full agonism-associated side effects. PPARγ ligands that act through the blockage of PPARγ phosphorylation but lack the full agonist activity would be expected to improve insulin sensitivity without TZD-associated side effects, however, chemicals that carry such traits and bind to PPARγ with high-affinity are lacking. Moreover, TZDs are known to promote white-to-brown adipocyte conversion and energy expenditure and appear to require their full agonism on PPARγ for this activity. It is unknown whether a partial or non-TZD agonist of PPARγ is capable of promoting browning effect. In this study, we developed a novel non-TZD partial agonist of PPARγ and investigated its function on insulin sensitivity and white-to-brown conversion and energy expenditure in diet-induced obese mice. Methods A novel indole-based chemical WO95E was designed via medicinal chemistry and tested for PPARγ binding and activity and for the effect on PPARγ phosphorylation. Diet-induced obese mice were admin

Evidence level

Evidence from laboratory and animal studies provides groundwork for understanding mechanisms and potential before human studies continue.

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