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

doi:10.1038/ncomms12733

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

Department of Oral Biology

Research output: Contribution to journal › Article › peer-review

26 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 language	English
Article number	12733
Journal	Nature communications
Volume	7
DOIs	https://doi.org/10.1038/ncomms12733
Publication status	Published - 2016 Sept 29

Bibliographical note

Funding Information:
We thank Dr Domenico Accili (Columbia University Medical Center, NY, USA) for providing all the FoxO1 plasmids and Ju-Hye Park (Wonju College of Medicine, Yonsei University) for brain illustrations. This research was supported by the National Research Foundation; NRF-2015H1A2A1032009 (to D.J.Y.); NRF-2013R1A1A1007693 and NRF-2016R1C1B3012748 (to K.W.K.).

Publisher Copyright:
© The Author(s) 2016.

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

@article{d853c89946a344cea76913937334657d,

title = "FoxO1 in dopaminergic neurons regulates energy homeostasis and targets tyrosine hydroxylase",

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.",

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

note = "Funding Information: We thank Dr Domenico Accili (Columbia University Medical Center, NY, USA) for providing all the FoxO1 plasmids and Ju-Hye Park (Wonju College of Medicine, Yonsei University) for brain illustrations. This research was supported by the National Research Foundation; NRF-2015H1A2A1032009 (to D.J.Y.); NRF-2013R1A1A1007693 and NRF-2016R1C1B3012748 (to K.W.K.). Publisher Copyright: {\textcopyright} The Author(s) 2016.",

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doi = "10.1038/ncomms12733",

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AU - Doan, Khanh V.

AU - Kinyua, Ann W.

AU - Yang, Dong Joo

AU - Ko, Chang Mann

AU - Moh, Sang Hyun

AU - Shong, Ko Eun

AU - Kim, Hail

AU - Park, Sang Kyu

AU - Kim, Dong Hoon

AU - Kim, Inki

AU - Paik, Ji Hye

AU - Depinho, Ronald A.

AU - Yoon, Seul Gi

AU - Kim, Il Yong

AU - Seong, Je Kyung

AU - Choi, Yun Hee

AU - Kim, Ki Woo

N1 - Funding Information: We thank Dr Domenico Accili (Columbia University Medical Center, NY, USA) for providing all the FoxO1 plasmids and Ju-Hye Park (Wonju College of Medicine, Yonsei University) for brain illustrations. This research was supported by the National Research Foundation; NRF-2015H1A2A1032009 (to D.J.Y.); NRF-2013R1A1A1007693 and NRF-2016R1C1B3012748 (to K.W.K.). Publisher Copyright: © The Author(s) 2016.

PY - 2016/9/29

Y1 - 2016/9/29

N2 - 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.

AB - 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.

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FoxO1 in dopaminergic neurons regulates energy homeostasis and targets tyrosine hydroxylase

Abstract

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