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 () and Ki Woo Kim ()
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Khanh V. Doan: Wonju College of Medicine, Yonsei University
Ann W. Kinyua: Wonju College of Medicine, Yonsei University
Dong Joo Yang: Wonju College of Medicine, Yonsei University
Chang Mann Ko: Wonju College of Medicine, Yonsei University
Sang Hyun Moh: Anti-aging Research Institute of BIO-FD&C Co. Ltd.
Ko Eun Shong: Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology
Hail Kim: Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology
Sang-Kyu Park: College of Medicine, Catholic Kwandong University
Dong-Hoon Kim: Korea University College of Medicine
Inki Kim: Asan Institute for Life Sciences, Asan Medical Center
Ji-Hye Paik: Weill Cornell Medical College
Ronald A. DePinho: University of Texas MD Anderson Cancer Center
Seul Gi Yoon: Laboratory of Developmental Biology and Genetics, College of Veterinary Medicine, Research Institute for Veterinary Science
Il Yong Kim: Laboratory of Developmental Biology and Genetics, College of Veterinary Medicine, Research Institute for Veterinary Science
Je Kyung Seong: Laboratory of Developmental Biology and Genetics, College of Veterinary Medicine, Research Institute for Veterinary Science
Yun-Hee Choi: Anti-aging Research Institute of BIO-FD&C Co. Ltd.
Ki Woo Kim: Wonju College of Medicine, Yonsei University

Nature Communications, 2016, vol. 7, issue 1, 1-12

Abstract: 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 KODAT) show markedly increased energy expenditure and interscapular brown adipose tissue (iBAT) thermogenesis accompanied by reduced fat mass and improved glucose/insulin homoeostasis. Moreover, FoxO1 KODAT 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.

Date: 2016
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DOI: 10.1038/ncomms12733

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