Activators of peroxisome proliferator-activated receptor-γ (PPARγ), which sensitize tissues to insulin, are widely used to treat type II diabetes. The realization that these drugs also reduce inflammation (see recent Live Discussion on PPARγ and AD) raised hope that they may prove beneficial for patients with neurologic disorders accompanied by inflammation. Together with other research, this has prompted clinical trials of pioglitazone and rosiglitazone in Alzheimer's patients (see ARF related news story). Those following this story may want to take note of the new finding that activation of PPARγ's cousin PPARδ may spur the development of intestinal cancers in mice. The brief report by Raymond DuBois and colleagues from the Vanderbilt University School of Medicine, Nashville, appears in the February Nature Medicine.

First author Rajnish Gupta and colleagues administered the PPARδ agonist GW501516 to mice lacking the adenomatous polyposis coli (APC) tumor suppressor; these animals have a high risk for colorectal cancers. The drug led to a significant increase in both the size and number of intestinal polyps. Control mice had, on average, 28 small-intestine polyps, whereas drug-treated animals had twice as many. When the authors counted polyps over 2 mm in diameter, however, they found a 10-fold greater incidence in the treated animals, suggesting that the agonist lead to an increase in polyp size.

While the authors caution that PPARδ agonists should be evaluated fully for proneoplastic effects before they are used in the clinic, there is no indication that activation of PPARγ pathways play a role in polyp growth. In fact, the authors explicitly state that GW501516 is a subtype-selective agonist for the PPAR family, binding only to the δ isoform.—Tom Fagan

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References

News Citations

  1. Orlando: Early Results Hint That Insulin-Sensitizing Drug Improves Cognition

Other Citations

  1. Live Discussion

Further Reading

Primary Papers

  1. . Activation of nuclear hormone receptor peroxisome proliferator-activated receptor-delta accelerates intestinal adenoma growth. Nat Med. 2004 Mar;10(3):245-7. PubMed.