FoxO1 regulates leptin-induced mood behavior by targeting tyrosine hydroxylase

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

Research output: Contribution to journalArticle

2 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)43-52
Number of pages10
JournalMetabolism: Clinical and Experimental
Volume91
DOIs
Publication statusPublished - 2019 Feb

Fingerprint

Tyrosine 3-Monooxygenase
Leptin
STAT3 Transcription Factor
Dopaminergic Neurons
Anti-Anxiety Agents
Mesencephalon
Dopamine
Anxiety
Depression
Phenotype

All Science Journal Classification (ASJC) codes

  • Endocrinology, Diabetes and Metabolism
  • Endocrinology

Cite this

Son, Dong Hwee ; Doan, Khanh V. ; Yang, Dong Joo ; Sun, Ji Su ; Kim, Seul Ki ; Kang, Namju ; Kang, Jung Yun ; Paik, Ji Hye ; DePinho, Ronald A. ; Choi, Yun Hee ; Shin, Dong Min ; Kim, Ki Woo. / FoxO1 regulates leptin-induced mood behavior by targeting tyrosine hydroxylase. In: Metabolism: Clinical and Experimental. 2019 ; Vol. 91. pp. 43-52.
@article{3042e3da195946848dea068d08fa31dd,
title = "FoxO1 regulates leptin-induced mood behavior by targeting 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.",
author = "Son, {Dong Hwee} and Doan, {Khanh V.} and Yang, {Dong Joo} and Sun, {Ji Su} and Kim, {Seul Ki} and Namju Kang and Kang, {Jung Yun} and Paik, {Ji Hye} and DePinho, {Ronald A.} and Choi, {Yun Hee} and Shin, {Dong Min} and Kim, {Ki Woo}",
year = "2019",
month = "2",
doi = "10.1016/j.metabol.2018.11.013",
language = "English",
volume = "91",
pages = "43--52",
journal = "Metabolism: Clinical and Experimental",
issn = "0026-0495",
publisher = "W.B. Saunders Ltd",

}

Son, DH, Doan, KV, Yang, DJ, Sun, JS, Kim, SK, Kang, N, Kang, JY, Paik, JH, DePinho, RA, Choi, YH, Shin, DM & Kim, KW 2019, 'FoxO1 regulates leptin-induced mood behavior by targeting tyrosine hydroxylase', Metabolism: Clinical and Experimental, vol. 91, pp. 43-52. https://doi.org/10.1016/j.metabol.2018.11.013

FoxO1 regulates leptin-induced mood behavior by targeting tyrosine hydroxylase. / Son, Dong Hwee; Doan, Khanh V.; Yang, Dong Joo; Sun, Ji Su; Kim, Seul Ki; Kang, Namju; Kang, Jung Yun; Paik, Ji Hye; DePinho, Ronald A.; Choi, Yun Hee; Shin, Dong Min; Kim, Ki Woo.

In: Metabolism: Clinical and Experimental, Vol. 91, 02.2019, p. 43-52.

Research output: Contribution to journalArticle

TY - JOUR

T1 - FoxO1 regulates leptin-induced mood behavior by targeting tyrosine hydroxylase

AU - Son, Dong Hwee

AU - Doan, Khanh V.

AU - Yang, Dong Joo

AU - Sun, Ji Su

AU - Kim, Seul Ki

AU - Kang, Namju

AU - Kang, Jung Yun

AU - Paik, Ji Hye

AU - DePinho, Ronald A.

AU - Choi, Yun Hee

AU - Shin, Dong Min

AU - Kim, Ki Woo

PY - 2019/2

Y1 - 2019/2

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85057817914&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85057817914&partnerID=8YFLogxK

U2 - 10.1016/j.metabol.2018.11.013

DO - 10.1016/j.metabol.2018.11.013

M3 - Article

C2 - 30500562

AN - SCOPUS:85057817914

VL - 91

SP - 43

EP - 52

JO - Metabolism: Clinical and Experimental

JF - Metabolism: Clinical and Experimental

SN - 0026-0495

ER -