FoxO1 in dopaminergic neurons regulates energy homeostasis and targets tyrosine hydroxylase.
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 KODATmice 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.
Department of Pharmacology, Wonju College of Medicine, Yonsei University, Wonju 26426, Korea.|Department of Global Medical Science, Wonju College of Medicine, Yonsei University, Wonju 26426, Korea.|School of Pharmacy, University of Medicine and Pharmacy-Ho Chi Minh, 41 Dinh Tien Hoang, District 1, Ho Chi Minh city 700000, Vietnam.
Khanh V
KV
Doan
Department of Pharmacology, Wonju College of Medicine, Yonsei University, Wonju 26426, Korea.|Department of Global Medical Science, Wonju College of Medicine, Yonsei University, Wonju 26426, Korea.
Ann W
AW
Kinyua
Department of Pharmacology, Wonju College of Medicine, Yonsei University, Wonju 26426, Korea.|Department of Global Medical Science, Wonju College of Medicine, Yonsei University, Wonju 26426, Korea.
Dong Joo
DJ
Yang
Department of Pharmacology, Wonju College of Medicine, Yonsei University, Wonju 26426, Korea.
Chang Mann
CM
Ko
Anti-aging Research Institute of BIO-FD&C Co. Ltd., Incheon 21990, Korea.
Sang Hyun
SH
Moh
Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon 34141, Korea.
Ko Eun
http://orcid.org/0000-0002-2677-8537
KE
Shong
Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon 34141, Korea.
Hail
H
Kim
Department of Biochemistry, College of Medicine, Catholic Kwandong University, Gangneung 25601 Korea.
Sang-Kyu
SK
Park
Department of Pharmacology, Korea University College of Medicine, Seoul 02841, Korea.
Dong-Hoon
DH
Kim
Asan Institute for Life Sciences, Asan Medical Center, Seoul 05535, Korea.
Inki
I
Kim
Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, New York 10065, USA.
Ji-Hye
JH
Paik
Department of Cancer Biology, University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
Ronald A
RA
DePinho
Laboratory of Developmental Biology and Genetics, College of Veterinary Medicine, Research Institute for Veterinary Science, Seoul 08826, Korea.|Korea Mouse Phenotyping Center, Seoul 08826, Korea.
Seul Gi
SG
Yoon
Laboratory of Developmental Biology and Genetics, College of Veterinary Medicine, Research Institute for Veterinary Science, Seoul 08826, Korea.|Korea Mouse Phenotyping Center, Seoul 08826, Korea.
Il Yong
IY
Kim
Laboratory of Developmental Biology and Genetics, College of Veterinary Medicine, Research Institute for Veterinary Science, Seoul 08826, Korea.|Korea Mouse Phenotyping Center, Seoul 08826, Korea.|BK21Plus Program for Creative Veterinary Science Research, BIO-MAX institute, Interdisciplinary Program for Bioinformatics, and Program for Cancer Biology, Seoul National University, Seoul 08826, Korea.
Je Kyung
JK
Seong
Anti-aging Research Institute of BIO-FD&C Co. Ltd., Incheon 21990, Korea.
Yun-Hee
YH
Choi
Department of Pharmacology, Wonju College of Medicine, Yonsei University, Wonju 26426, Korea.|Department of Global Medical Science, Wonju College of Medicine, Yonsei University, Wonju 26426, Korea.
Ki Woo
KW
Kim
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