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Hepatic thyroid hormone signalling modulates glucose homeostasis through the regulation of GLP-1 production via bile acid-mediated FXR antagonism

文献类型：期刊论文

作者Yan, Ying10,11; Niu, Zhoumin10,11; Sun, Chao10,11; Li, Peng10,11; Shen, Siyi10,11; Liu, Shengnan10,11; Wu, Yuting10,11; Yun, Chuyu9; Jiao, Tingying8; Jia, Sheng7
刊名NATURE COMMUNICATIONS
出版日期2022-10-27
卷号13期号:1页码:16
DOI10.1038/s41467-022-34258-w
通讯作者Jiang, Jingjing(jiang.jingjing@zs-hospital.sh.cn) ; Ying, Hao(yinghao@sibs.ac.cn)
英文摘要Thyroid hormones regulate systemic glucose metabolism through incompletely understood mechanisms. Here the authors report that hepatic thyroid hormone receptor beta mediates the effects of the thyroid hormone T3 on systemic glucose homeostasis by modulating GLP-1 levels through suppression of hepatic CYP8B1 expression and bile acid mediated inhibition of intestinal FXR signalling. Thyroid hormones (TH) regulate systemic glucose metabolism through incompletely understood mechanisms. Here, we show that improved glucose metabolism in hypothyroid mice after T3 treatment is accompanied with increased glucagon-like peptide-1 (GLP-1) production and insulin secretion, while co-treatment with a GLP-1 receptor antagonist attenuates the effects of T3 on insulin and glucose levels. By using mice lacking hepatic TH receptor beta (TR beta) and a liver-specific TR beta-selective agonist, we demonstrate that TR beta-mediated hepatic TH signalling is required for both the regulation of GLP-1 production and the insulinotropic and glucose-lowering effects of T3. Moreover, administration of a liver-targeted TR beta-selective agonist increases GLP-1 and insulin levels and alleviates hyperglycemia in diet-induced obesity. Mechanistically, T3 suppresses Cyp8b1 expression, resulting in increased the levels of Farnesoid X receptor (FXR)-antagonistic bile acids, thereby potentiating GLP-1 production and insulin secretion by repressing intestinal FXR signalling. T3 correlates with both plasma GLP-1 and fecal FXR-antagonistic bile acid levels in people with normal thyroid function. Thus, our study reveals a role for hepatic TH signalling in glucose homeostasis through the regulation of GLP-1 production via bile acid-mediated FXR antagonism.
WOS关键词FARNESOID-X-RECEPTOR ; NUCLEAR COREPRESSOR ; METABOLISM ; LIVER ; CHOLESTEROL ; GLUCAGON ; INSULIN ; MICROBIOTA ; IMPROVES ; OBESITY
资助项目National Key Research and Development Program of China[2021YFA1100500] ; National NSFC[91957205] ; National NSFC[82070821] ; National NSFC[81970748] ; Pujiang Talent Program from STCSM[21PJ1416100] ; Youth Innovation Promotion Association, CAS[2021261] ; NHC Key Laboratory of Food Safety Risk Assessment[2020K02] ; Nature Science Foundation of Shanghai[202R1444400] ; Collaborative Innovation Center of Food Safety and Quality Control in Jiangsu Province, Jiangnan University[2022-3-1]
WOS研究方向Science & Technology - Other Topics
语种英语
出版者NATURE PORTFOLIO
WOS记录号WOS:000875724400026
源URL[http://119.78.100.183/handle/2S10ELR8/302996]  
专题新药研究国家重点实验室
通讯作者Jiang, Jingjing; Ying, Hao
作者单位1.Minist Hlth, Key Lab Food Safety Risk Assessment, Shanghai 200031, Peoples R China
2.Shanghai Jiao Tong Univ Affiliated Peoples Hosp 6, Shanghai Clin Ctr Diabet, Shanghai Diabet Inst, Shanghai Key Lab Diabet Mellitus, Shanghai 200233, Peoples R China
3.Shanghai Jiao Tong Univ, Shanghai Gen Hosp, Sch Med, Dept Endocrinol & Metab, Shanghai 200080, Peoples R China
4.Jiangnan Univ, Sch Food Sci & Technol, State Key Lab Food Sci & Technol, Wuxi 214122, Jiangsu, Peoples R China
5.Fudan Univ, Zhongshan Hosp, Dept Endocrinol & Metab, Shanghai 200031, Peoples R China
6.Tianjin Med Univ, Sch Publ Hlth, Dept Toxicol & Sanit Chem, Tianjin 300070, Peoples R China
7.Shanghai Jiao Tong Univ, Ruijin Hosp, Dept Endocrinol & Metab,Sch Med, Key Lab Endocrine & Metab Dis Chinese Hlth Commis, Shanghai 200025, Peoples R China
8.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China
9.Peking Univ, Sch Basic Med Sci, Dept Physiol & Pathophysiol, Beijing 100191, Peoples R China
10.Shanghai Jiao Tong Univ Affiliated Peoples Hosp 6, Shanghai, Peoples R China
推荐引用方式
GB/T 7714		 Yan, Ying,Niu, Zhoumin,Sun, Chao,et al. Hepatic thyroid hormone signalling modulates glucose homeostasis through the regulation of GLP-1 production via bile acid-mediated FXR antagonism[J]. NATURE COMMUNICATIONS,2022,13(1):16.
APA Yan, Ying.,Niu, Zhoumin.,Sun, Chao.,Li, Peng.,Shen, Siyi.,...&Ying, Hao.(2022).Hepatic thyroid hormone signalling modulates glucose homeostasis through the regulation of GLP-1 production via bile acid-mediated FXR antagonism.NATURE COMMUNICATIONS,13(1),16.
MLA Yan, Ying,et al."Hepatic thyroid hormone signalling modulates glucose homeostasis through the regulation of GLP-1 production via bile acid-mediated FXR antagonism".NATURE COMMUNICATIONS 13.1(2022):16.

入库方式： OAI收割

来源：上海药物研究所

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