'No, really, how do they work?' (original) (raw)

1. David D. Moore
2. Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas 77030, USA

“How do the antidiabetic thiazolidinediones work?” If your 3-yr-old asked this question it would be easy to answer: “They function as agonists to activate PPARγ.” Inquisitive minds being what they are, this answer would suffice only for a moment and a more incisive query would soon follow: “But how does PPARγ activation affect diabetes?” You could keep the cycle going for another round by responding: “When it is activated, PPARγ turns on the expression of appropriate target genes that function to increase insulin sensitivity.” And you might manage to delay the inevitable by handing her a printout of PPARγ targets identified by gene arrays. But 3-yr-olds are not easily sidetracked by such obvious ploys and you would soon face the inevitable “No, really, how do they work?”

In this issue, Lazar and colleagues (Guan et al. 2005) add an intriguing new answer that moves beyond some stereotypic assumptions about PPARγ and nuclear receptors. But appreciating it requires some examination of these assumptions.

Pioglitazone (Actos) and rosiglitazone (Avandia) are related thiazolidinedione (TZD) compounds that are widely prescribed insulin sensitizers, with yearly sales of each exceeding a billion dollars. Although they are indeed quite specific PPARγ agonists, they were not initially discovered by modern high-throughput screening approaches, as one might assume, but in decidedly lowthroughput animal-based screens for effects on insulin resistance (Fujita et al. 1983). Their identification as PPARγ activators was based on the guesses of several groups (Forman et al. 1995; Lehmann et al. 1995) who managed to link …