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

Abstract

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.

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Figure 1: FoxO1 is expressed in Pomc and Agrp neurons.
Figure 2: Localization of FoxO1-ADA after stereotactic delivery.
Figure 3: Effects of FoxO1-ADA on food intake and neuropeptide expression.
Figure 4: Effects of loss of FoxO1 function on food intake and neuropeptide expression.
Figure 5: FoxO1 and Stat3 bind to adjacent sequences in the Agrp and Pomc promoters.
Figure 6: FoxO1 and Stat3 effect opposing actions on Agrp and Pomc promoters.

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Acknowledgements

Supported by National Institutes of Health grants DK57539 (to D.A.), DK45024 DK48321 and AG 21654 (to L.R.), DK63608 (Columbia Diabetes and Endocrinology Research Center) and DK20541 (Einstein Diabetes Research and Training Center). We thank members of the Accili and Rossetti laboratories for discussions.

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Correspondence to Domenico Accili.

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The authors declare no competing financial interests.

Supplementary information

Supplementary Fig. 1

FoxO1 localization in Agrp neurons in response to fasting and refeeding. (PDF 241 kb)

Supplementary Fig. 2

Survey of FoxO1 localization following adenoviral delivery. (PDF 234 kb)

Supplementary Fig. 3

Feeding studies in response to intraperitoneal leptin. (PDF 51 kb)

Supplementary Fig. 4

FoxO1-ADA and Δ256 fail to affect Pomc mRNA expression levels. (PDF 54 kb)

Supplementary Fig. 5

Western blot analysis of FoxO1 levels in hypothalami from wild-type and Foxo1+/− mice. (PDF 29 kb)

Supplementary Fig. 6

Mobility gel-shift assays in the presence of varying amounts of bacterially expressed FoxO1 or Stat3 incubated in vitro with radiolabeled oligonucleotides spanning the FoxO1 and Stat3 binding sites of Agrp or Pomc. (PDF 64 kb)

Supplementary Fig. 7

Quantitative analysis of Agrp ChIP assay. (PDF 55 kb)

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Kitamura, T., Feng, Y., Ido Kitamura, Y. et al. Forkhead protein FoxO1 mediates Agrp-dependent effects of leptin on food intake. Nat Med 12, 534–540 (2006). https://doi.org/10.1038/nm1392

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