Forkhead protein FoxO1 mediates Agrp-dependent effects of leptin on food intake.

Leptin controls food intake by regulating the transcription of key neuropeptides in the hypothalamus. The mechanism by which leptin regulates gene expression is unclear, however. Here we show that delivery of adenovirus encoding a constitutively nuclear mutant FoxO1, a transcription factor known to control liver metabolism and pancreatic beta-cell function, to the hypothalamic arcuate nucleus of rodents results in a loss of the ability of leptin to curtail food intake and suppress expression of Agrp. Conversely, a transactivation-deficient FoxO1 mutant prevents induction of Agrp by fasting. We also find that FoxO1 and the transcription factor Stat3 exert opposing actions on the expression of Agrp and Pomc through transcriptional squelching. FoxO1 promotes opposite patterns of coactivator-corepressor exchange at the Pomc and Agrp promoters, resulting in activation of Agrp and inhibition of Pomc. Thus, FoxO1 represents a shared component of pathways integrating food intake and peripheral metabolism.