PPARγ agonists induce biased signaling in human adipocytes

Biased signaling and ligand bias, often referred to as functional selectivity or selective nuclear receptor modulation, have been reported for many nuclear receptor partial agonists over the past 20 years. However, whether differences in nuclear receptor signaling produced by partial and full agonists results from less intense partial agonist modulation, off-target effects, or biased signaling remains unclear. To determine whether biased signaling can occur through nuclear receptors we compare the transcriptional effects of two full agonists (which also favor different coactivator peptides) in human adipocytes. We also test the signaling effects of a partial agonist relative to full agonists. Furthermore, whether biased coactivator peptide recruitment translates to biased signaling in cells has not been determined. In a step towards this goal, we show that these same full agonists induce biased recruitment of 100-300 residue regions of coactivators containing all their nuclear receptor binding motifs. Together these data support the idea that nuclear receptor agonists can induce biased signaling through differences in coactivator recruitment.