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The nuclear receptor peroxisome proliferator-activated receptor-gamma (PPARgamma) helps to translate 'what you eat' into 'what you are' because it allows dietary fatty acids (PPARgamma ligands) to modulate gene transcription. Treatments for diabetes include PPARgamma activators, as they sensitize the body to insulin. Our understanding of PPARgamma function has recently been enhanced by a flurry of human and mouse genetic studies, and the characterization of new PPARgamma ligands. This insight has led us to propose that modulating PPARgamma activity, rather than activating it, might be the most effective strategy for treating metabolic disorders, as this will improve glucose homeostasis while preventing adipogenesis.