FoxO1 in dopaminergic neurons regulates energy homeostasis and targets tyrosine hydroxylase

Khanh V. Doan, Ann W. Kinyua, Dong Joo Yang, Chang Mann Ko, Sang Hyun Moh, Ko Eun Shong, Hail Kim, Sang Kyu Park, Dong Hoon Kim, Inki Kim, Ji Hye Paik, Ronald A. Depinho, Seul Gi Yoon, Il Yong Kim, Je Kyung Seong, Yun Hee Choi, Ki Woo Kim

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15 Citations (Scopus)

Abstract

Dopaminergic (DA) neurons are involved in the integration of neuronal and hormonal signals to regulate food consumption and energy balance. Forkhead transcriptional factor O1 (FoxO1) in the hypothalamus plays a crucial role in mediation of leptin and insulin function. However, the homoeostatic role of FoxO1 in DA system has not been investigated. Here we report that FoxO1 is highly expressed in DA neurons and mice lacking FoxO1 specifically in the DA neurons (FoxO1 KO DAT) show markedly increased energy expenditure and interscapular brown adipose tissue (iBAT) thermogenesis accompanied by reduced fat mass and improved glucose/insulin homoeostasis. Moreover, FoxO1 KO DAT mice exhibit an increased sucrose preference in concomitance with higher dopamine and norepinephrine levels. Finally, we found that FoxO1 directly targets and negatively regulates tyrosine hydroxylase (TH) expression, the rate-limiting enzyme of the catecholamine synthesis, delineating a mechanism for the KO phenotypes. Collectively, these results suggest that FoxO1 in DA neurons is an important transcriptional factor that directs the coordinated control of energy balance, thermogenesis and glucose homoeostasis.

Original languageEnglish
Article number12733
JournalNature communications
Volume7
DOIs
Publication statusPublished - 2016 Sep 29

All Science Journal Classification (ASJC) codes

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

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    Doan, K. V., Kinyua, A. W., Yang, D. J., Ko, C. M., Moh, S. H., Shong, K. E., Kim, H., Park, S. K., Kim, D. H., Kim, I., Paik, J. H., Depinho, R. A., Yoon, S. G., Kim, I. Y., Seong, J. K., Choi, Y. H., & Kim, K. W. (2016). FoxO1 in dopaminergic neurons regulates energy homeostasis and targets tyrosine hydroxylase. Nature communications, 7, [12733]. https://doi.org/10.1038/ncomms12733