Rosiglitazone, a type 2 diabetes drug, increases food intake and improves liver metabolism through its actions in the brain, according to two reports published this week in Nature Medicine. These results suggest that while some of the negative effects of rosiglitazone are due to its action in the brain, so are some of its positive effects. These are important insights if this class of drug is to be reformulated to avoid the cardiovascular side-effects that recently resulted in rosiglitazone’s restricted use in the clinic.
Randy Seeley and his colleagues show that in mice the drug rosiglitazone activates a transcription factor, PPAR-gamma, in the brain to increase food intake and fat mass.
In the second report, Jerrold Olefsky and his colleagues find that genetically knocking out PPAR-gamma in mice results in reduced food intake and fat mass, compared to normal mice when both are fed a high-fat diet. Surprisingly, however, even though the knockout mice gain less weight on a high fat diet, their insulin sensitivity in the liver is worse than wild-type controls. Likewise, the authors also find that the increase in body fat that is often seen in people taking rosiglitazone is blunted in the knockout mice, but so are the insulin-sensitizing effects of the drug.