FoxO1 regulates leptin-induced mood behavior by targeting tyrosine hydroxylase

• Published in: Metabolism, clinical and experimental clinical and experimental, 2019-02, Vol.91, p.43-52
• Main Authors: 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
• Format: Article
• Language: English
• Subjects: Anxiolytic; Dopaminergic neuron; Forkhead transcriptional factor O1; Leptin; Midbrain; Signal transducer and activator of transcription 3; Tyrosine hydroxylase
• ISSN: 0026-0495; 1532-8600
• DOI: 10.1016/j.metabol.2018.11.013

While leptin has been associated with various psycho-physiological functions, the molecular network in leptin-mediated mood regulation remains elusive. 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. 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. 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. •TH increment by leptin is via STAT3 activation and FoxO1 inhibition in midbrain.•FoxO1 inhibition by leptin is a key in leptin-induced anxiolytic-like behavior.•FoxO1 KODAT mice showed enhanced leptin sensitivity and anxiolytic-like behavior.