PPARγ, an X‐ceptor for Xs

A bstract : Evidence from both human genetic studies and characterization of peroxisome proliferator‐activated receptor gamma (PPARγ) knockout mice suggested that the prime function of PPARγ is fat formation and that its role in insulin sensitization might be secondary to this function. The thrifty function of PPARγ was most likely evolutionary beneficial, but might in “times of plenty” contribute to the pathogenesis of disorders, such as obesity, insulin resistance, type 2 diabetes, and hyperlipidemia, often commonly referred to as “syndrome X”. This role of PPARγ in these diseases also questions the eventual therapeutic benefits of pure PPARγ activation, which is associated with an increase in adipose tissue mass. We characterized a new chemical class of PPARγ agonists, that is, FMOC‐l‐leucine (FLL). FLL induces a different conformation of PPARγ relative to classical PPARγ ligands. Mass spectrometry indicates that two molecules of FLL bind to a single PPARγ molecule, making its mode of receptor interaction distinctive. FLL recruits a different set of coactivators and activates PPARγ with a lower potency, but a similar maximal efficacy, relative to known PPARγ ligands. In contrast, FLL is a more effective insulin sensitizer than current PPARγ agonists, an effect potentially linked to its weak adipogenic activity. These data make a strong point for potential therapeutic benefits of PPARγ modulation rather than activation.