FoxO1 in dopaminergic neurons regulates energy homeostasis and targets tyrosine hydroxylase

被引:40
作者
Doan, Khanh V. [1 ,2 ,3 ]
Kinyua, Ann W. [1 ,2 ]
Yang, Dong Joo [1 ,2 ]
Ko, Chang Mann [1 ]
Moh, Sang Hyun [4 ]
Shong, Ko Eun [5 ]
Kim, Hail [5 ]
Park, Sang-Kyu [6 ]
Kim, Dong-Hoon [7 ]
Kim, Inki [8 ]
Paik, Ji-Hye [9 ]
DePinho, Ronald A. [10 ]
Yoon, Seul Gi [11 ,12 ]
Kim, Il Yong [11 ,12 ]
Seong, Je Kyung [11 ,12 ,13 ,14 ]
Choi, Yun-Hee [4 ]
Kim, Ki Woo [1 ,2 ]
机构
[1] Yonsei Univ, Wonju Coll Med, Dept Pharmacol, Wonju 26426, South Korea
[2] Yonsei Univ, Wonju Coll Med, Dept Global Med Sci, Wonju 26426, South Korea
[3] Univ Med & Pharm Ho Chi Minh, Sch Pharm, 41 Dinh Tien Hoang,Dist 1, Ho Chi Minh City 700000, Vietnam
[4] BIO FD&C Co Ltd, Antiaging Res Inst, Inchon 21990, South Korea
[5] Korea Adv Inst Sci & Technol, Grad Sch Med Sci & Engn, Daejeon 34141, South Korea
[6] Catholic Kwandong Univ, Coll Med, Dept Biochem, Kangnung 25601, South Korea
[7] Korea Univ, Dept Pharmacol, Coll Med, Seoul 02841, South Korea
[8] Asan Med Ctr, Asan Inst Life Sci, Seoul 05535, South Korea
[9] Weill Cornell Med Coll, Dept Pathol & Lab Med, New York, NY 10065 USA
[10] Univ Texas MD Anderson Canc Ctr, Dept Canc Biol, Houston, TX 77030 USA
[11] Res Inst Vet Sci, Coll Vet Med, Lab Dev Biol & Genet, Seoul 08826, South Korea
[12] Korea Mouse Phenotyping Ctr, Seoul 08826, South Korea
[13] Seoul Natl Univ, Interdisciplinary Program Bioinformat, BIOMAX Inst, Program Creat Vet Sci Res BK21Plus, Seoul 08826, South Korea
[14] Seoul Natl Univ, Program Canc Biol, Seoul 08826, South Korea
来源
NATURE COMMUNICATIONS | 2016年 / 7卷
基金
新加坡国家研究基金会;
关键词
BROWN ADIPOSE-TISSUE; ORPHAN NUCLEAR RECEPTOR; VENTRAL TEGMENTAL AREA; MICE LACKING FOXO1; FOOD-INTAKE; GLUCOSE-HOMEOSTASIS; INSULIN SENSITIVITY; TRANSCRIPTION FACTORS; HYPOTHALAMIC FOXO1; LOCOMOTOR-ACTIVITY;
D O I
10.1038/ncomms12733
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
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.
引用
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页数:12
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