ADGRA1 negatively regulates energy expenditure and thermogenesis through both sympathetic nervous system and hypothalamus–pituitary–thyroid axis in male mice
Abstract Adhesion G protein-coupled receptor A1 (ADGRA1, also known as GPR123) belongs to the G protein-coupled receptors (GPCRs) family and is well conserved in the vertebrate lineage. However, the structure of ADGRA1 is unique and its physiological function remains unknown. Previous studies have s...
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Nature Publishing Group
2021-04-01
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Series: | Cell Death and Disease |
Online Access: | https://doi.org/10.1038/s41419-021-03634-7 |
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Article |
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DOAJ |
language |
English |
format |
Article |
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DOAJ |
author |
Xiao-Hong Zhang Ling-Yun Tang Xi-Yi Wang Chun-Ling Shen Wen-Feng Xiong Yan Shen Ying-Han Wan You-Bing Wu Yi-Cheng Wang Hong-Xin Zhang Shun-Yuan Lu Jian Fei Zhu-Gang Wang |
spellingShingle |
Xiao-Hong Zhang Ling-Yun Tang Xi-Yi Wang Chun-Ling Shen Wen-Feng Xiong Yan Shen Ying-Han Wan You-Bing Wu Yi-Cheng Wang Hong-Xin Zhang Shun-Yuan Lu Jian Fei Zhu-Gang Wang ADGRA1 negatively regulates energy expenditure and thermogenesis through both sympathetic nervous system and hypothalamus–pituitary–thyroid axis in male mice Cell Death and Disease |
author_facet |
Xiao-Hong Zhang Ling-Yun Tang Xi-Yi Wang Chun-Ling Shen Wen-Feng Xiong Yan Shen Ying-Han Wan You-Bing Wu Yi-Cheng Wang Hong-Xin Zhang Shun-Yuan Lu Jian Fei Zhu-Gang Wang |
author_sort |
Xiao-Hong Zhang |
title |
ADGRA1 negatively regulates energy expenditure and thermogenesis through both sympathetic nervous system and hypothalamus–pituitary–thyroid axis in male mice |
title_short |
ADGRA1 negatively regulates energy expenditure and thermogenesis through both sympathetic nervous system and hypothalamus–pituitary–thyroid axis in male mice |
title_full |
ADGRA1 negatively regulates energy expenditure and thermogenesis through both sympathetic nervous system and hypothalamus–pituitary–thyroid axis in male mice |
title_fullStr |
ADGRA1 negatively regulates energy expenditure and thermogenesis through both sympathetic nervous system and hypothalamus–pituitary–thyroid axis in male mice |
title_full_unstemmed |
ADGRA1 negatively regulates energy expenditure and thermogenesis through both sympathetic nervous system and hypothalamus–pituitary–thyroid axis in male mice |
title_sort |
adgra1 negatively regulates energy expenditure and thermogenesis through both sympathetic nervous system and hypothalamus–pituitary–thyroid axis in male mice |
publisher |
Nature Publishing Group |
series |
Cell Death and Disease |
issn |
2041-4889 |
publishDate |
2021-04-01 |
description |
Abstract Adhesion G protein-coupled receptor A1 (ADGRA1, also known as GPR123) belongs to the G protein-coupled receptors (GPCRs) family and is well conserved in the vertebrate lineage. However, the structure of ADGRA1 is unique and its physiological function remains unknown. Previous studies have shown that Adgra1 is predominantly expressed in the central nervous system (CNS), indicating its important role in the transduction of neural signals. The aim of this study is to investigate the central function of Adgra1 in vivo and clarify its physiological significance by establishing an Adgra1-deficient mouse (Adgra1 −/− ) model. The results show that Adgra1 −/− male mice exhibit decreased body weight with normal food intake and locomotion, shrinkage of body mass, increased lipolysis, and hypermetabolic activity. Meanwhile, mutant male mice present elevated core temperature coupled with resistance to hypothermia upon cold stimulus. Further studies show that tyrosine hydroxylase (TH) and β3-adrenergic receptor (β3-AR), indicators of sympathetic nerve excitability, are activated as well as their downstream molecules including uncoupling protein 1 (UCP1), coactivator 1 alpha (PGC1-α) in brown adipose tissue (BAT), and hormone-sensitive lipase (HSL) in white adipose tissue (WAT). In addition, mutant male mice have higher levels of serum T3, T4, accompanied by increased mRNAs of hypothalamus–pituitary–thyroid axis. Finally, Adgra1 −/− male mice present abnormal activation of PI3K/AKT/GSK3β and MEK/ERK pathways in hypothalamus. Overexpression of ADGRA1 in Neuro2A cell line appears to suppress these two signaling pathways. In contrast, Adgra1 −/− female mice show comparable body weight along with normal metabolic process to their sex-matched controls. Collectively, ADGRA1 is a negative regulator of sympathetic nervous system (SNS) and hypothalamus–pituitary–thyroid axis by regulating PI3K/AKT/GSK3β and MEK/ERK pathways in hypothalamus of male mice, suggesting an important role of ADGRA1 in maintaining metabolic homeostasis including energy expenditure and thermogenic balance. |
url |
https://doi.org/10.1038/s41419-021-03634-7 |
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doaj-97c19a52993347bfb464ce2432306ff82021-04-11T11:05:12ZengNature Publishing GroupCell Death and Disease2041-48892021-04-0112411410.1038/s41419-021-03634-7ADGRA1 negatively regulates energy expenditure and thermogenesis through both sympathetic nervous system and hypothalamus–pituitary–thyroid axis in male miceXiao-Hong Zhang0Ling-Yun Tang1Xi-Yi Wang2Chun-Ling Shen3Wen-Feng Xiong4Yan Shen5Ying-Han Wan6You-Bing Wu7Yi-Cheng Wang8Hong-Xin Zhang9Shun-Yuan Lu10Jian Fei11Zhu-Gang Wang12School of Life Sciences and Biotechnology, Shanghai Jiao Tong UniversityState Key Laboratory of Medical Genomics, Research Center for Experimental Medicine, Rui-Jin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine (SJTUSM)State Key Laboratory of Medical Genomics, Research Center for Experimental Medicine, Rui-Jin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine (SJTUSM)State Key Laboratory of Medical Genomics, Research Center for Experimental Medicine, Rui-Jin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine (SJTUSM)School of Life Sciences and Biotechnology, Shanghai Jiao Tong UniversityState Key Laboratory of Medical Genomics, Research Center for Experimental Medicine, Rui-Jin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine (SJTUSM)Shanghai Engineering and Technology Research Center for Model Animals, Shanghai Model Organisms Center, Inc.Shanghai Engineering and Technology Research Center for Model Animals, Shanghai Model Organisms Center, Inc.Shanghai Engineering and Technology Research Center for Model Animals, Shanghai Model Organisms Center, Inc.State Key Laboratory of Medical Genomics, Research Center for Experimental Medicine, Rui-Jin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine (SJTUSM)State Key Laboratory of Medical Genomics, Research Center for Experimental Medicine, Rui-Jin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine (SJTUSM)Shanghai Engineering and Technology Research Center for Model Animals, Shanghai Model Organisms Center, Inc.School of Life Sciences and Biotechnology, Shanghai Jiao Tong UniversityAbstract Adhesion G protein-coupled receptor A1 (ADGRA1, also known as GPR123) belongs to the G protein-coupled receptors (GPCRs) family and is well conserved in the vertebrate lineage. However, the structure of ADGRA1 is unique and its physiological function remains unknown. Previous studies have shown that Adgra1 is predominantly expressed in the central nervous system (CNS), indicating its important role in the transduction of neural signals. The aim of this study is to investigate the central function of Adgra1 in vivo and clarify its physiological significance by establishing an Adgra1-deficient mouse (Adgra1 −/− ) model. The results show that Adgra1 −/− male mice exhibit decreased body weight with normal food intake and locomotion, shrinkage of body mass, increased lipolysis, and hypermetabolic activity. Meanwhile, mutant male mice present elevated core temperature coupled with resistance to hypothermia upon cold stimulus. Further studies show that tyrosine hydroxylase (TH) and β3-adrenergic receptor (β3-AR), indicators of sympathetic nerve excitability, are activated as well as their downstream molecules including uncoupling protein 1 (UCP1), coactivator 1 alpha (PGC1-α) in brown adipose tissue (BAT), and hormone-sensitive lipase (HSL) in white adipose tissue (WAT). In addition, mutant male mice have higher levels of serum T3, T4, accompanied by increased mRNAs of hypothalamus–pituitary–thyroid axis. Finally, Adgra1 −/− male mice present abnormal activation of PI3K/AKT/GSK3β and MEK/ERK pathways in hypothalamus. Overexpression of ADGRA1 in Neuro2A cell line appears to suppress these two signaling pathways. In contrast, Adgra1 −/− female mice show comparable body weight along with normal metabolic process to their sex-matched controls. Collectively, ADGRA1 is a negative regulator of sympathetic nervous system (SNS) and hypothalamus–pituitary–thyroid axis by regulating PI3K/AKT/GSK3β and MEK/ERK pathways in hypothalamus of male mice, suggesting an important role of ADGRA1 in maintaining metabolic homeostasis including energy expenditure and thermogenic balance.https://doi.org/10.1038/s41419-021-03634-7 |