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FoxO1 regulates leptin-induced mood behavior by targeting tyrosine hydroxylase

Authors
 Dong Hwee Son  ;  Khanh V. Doan  ;  Dong Joo Yang  ;  Ji Su Sun  ;  Seul Ki Kim  ;  Namju Kang  ;  Jung Yun Kang  ;  Ji-Hye Paik  ;  Ronald A. DePinho  ;  Yun-Hee Choi  ;  Dong Min Shin  ;  Ki Woo Kim 
Citation
 METABOLISM-CLINICAL AND EXPERIMENTAL, Vol.91 : 43-52, 2019 
Journal Title
 METABOLISM-CLINICAL AND EXPERIMENTAL 
ISSN
 0026-0495 
Issue Date
2019
Keywords
Anxiolytic ; Dopaminergic neuron ; Forkhead transcriptional factor O1 ; Leptin ; Midbrain ; Signal transducer and activator of transcription 3 ; Tyrosine hydroxylase
Abstract
PURPOSE: While leptin has been associated with various psycho-physiological functions, the molecular network in leptin-mediated mood regulation remains elusive. METHODS: Anxiolytic behaviors and tyrosine hydroxylase (TH) levels were examined after leptin administration. Functional roles of STAT3 and FoxO1 in regulation of TH expression were investigated using in vivo and in vitro systems. A series of animal behavioral tests using dopaminergic neuron-specific FoxO1 KO (FoxO1 KODAT) were performed and investigated the roles of FoxO1 in regulation of mood behaviors. RESULTS: Here, we show that administration of leptin induces anxiolytic-like phenotype through the activation of signal transducer and activator of transcription 3 (STAT3) and the inhibition of forkhead box protein O1 (FoxO1) in dopaminergic (DA) neurons of the midbrain. Specifically, STAT3 and FoxO1 directly bind to and exert opposing effects on tyrosine hydroxylase (TH) expression, where STAT3 acts as an enhancer and FoxO1 acts as a prominent repressor. Accordingly, suppression of the prominent suppressor FoxO1 by leptin strongly increased TH expression. Furthermore, our previous results showed that specific deletion of FoxO1 in DA neurons (FoxO1 KODAT) led to a profound elevation of TH activity and dopamine contents. Finally, FoxO1 KODAT mice exhibited enhanced leptin sensitivity as well as displayed reduced anxiety- and depression-like behaviors. CONCLUSIONS: This work establishes a novel molecular mechanism of mood behavior regulation by leptin and suggests FoxO1 suppression by leptin might be a key for leptin-induced behavioral manifestation in DA neurons.
Full Text
https://www.sciencedirect.com/science/article/pii/S002604951830252X
DOI
10.1016/j.metabol.2018.11.013
Appears in Collections:
2. College of Dentistry (치과대학) > Dept. of Oral Biology (구강생물학교실) > 1. Journal Papers
Yonsei Authors
Kim, Ki Woo(김기우) ORCID logo https://orcid.org/0000-0002-7790-1515
Shin, Dong Min(신동민) ORCID logo https://orcid.org/0000-0001-6042-0435
Choi, Yun Hee(최윤희) ORCID logo https://orcid.org/0000-0002-3519-8841
URI
https://ir.ymlib.yonsei.ac.kr/handle/22282913/167468
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