Cargando…

3-Hydroxybutyrate ameliorates insulin resistance by inhibiting PPARγ Ser273 phosphorylation in type 2 diabetic mice

3-Hydroxybutyrate (3HB) is a small ketone body molecule produced endogenously by the body in the liver. Previous studies have shown that 3HB can reduce blood glucose level in type 2 diabetic (T2D) patients. However, there is no systematic study and clear mechanism to evaluate and explain the hypogly...

Descripción completa

Detalles Bibliográficos
Autores principales: Zhang, Yudian, Li, Zihua, Liu, Xinyi, Chen, Xinyu, Zhang, Shujie, Chen, Yuemeng, Chen, Jiangnan, Chen, Jin, Wu, Fuqing, Chen, Guo-Qiang
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10212965/
https://www.ncbi.nlm.nih.gov/pubmed/37230992
http://dx.doi.org/10.1038/s41392-023-01415-6
_version_ 1785047526831816704
author Zhang, Yudian
Li, Zihua
Liu, Xinyi
Chen, Xinyu
Zhang, Shujie
Chen, Yuemeng
Chen, Jiangnan
Chen, Jin
Wu, Fuqing
Chen, Guo-Qiang
author_facet Zhang, Yudian
Li, Zihua
Liu, Xinyi
Chen, Xinyu
Zhang, Shujie
Chen, Yuemeng
Chen, Jiangnan
Chen, Jin
Wu, Fuqing
Chen, Guo-Qiang
author_sort Zhang, Yudian
collection PubMed
description 3-Hydroxybutyrate (3HB) is a small ketone body molecule produced endogenously by the body in the liver. Previous studies have shown that 3HB can reduce blood glucose level in type 2 diabetic (T2D) patients. However, there is no systematic study and clear mechanism to evaluate and explain the hypoglycemic effect of 3HB. Here we demonstrate that 3HB reduces fasting blood glucose level, improves glucose tolerance, and ameliorates insulin resistance in type 2 diabetic mice through hydroxycarboxylic acid receptor 2 (HCAR2). Mechanistically, 3HB increases intracellular calcium ion (Ca(2+)) levels by activating HCAR2, thereby stimulating adenylate cyclase (AC) to increase cyclic adenosine monophosphate (cAMP) concentration, and then activating protein kinase A (PKA). Activated PKA inhibits Raf1 proto-oncogene serine/threonine-protein kinase (Raf1) activity, resulting in a decrease in extracellular signal-regulated kinases 1/2 (ERK1/2) activity and ultimately inhibiting peroxisome proliferator-activated receptor γ (PPARγ) Ser273 phosphorylation in adipocytes. Inhibition of PPARγ Ser273 phosphorylation by 3HB altered the expression of PPARγ regulated genes and reduced insulin resistance. Collectively, 3HB ameliorates insulin resistance in type 2 diabetic mice through a pathway of HCAR2/Ca(2+)/cAMP/PKA/Raf1/ERK1/2/PPARγ.
format Online
Article
Text
id pubmed-10212965
institution National Center for Biotechnology Information
language English
publishDate 2023
publisher Nature Publishing Group UK
record_format MEDLINE/PubMed
spelling pubmed-102129652023-05-27 3-Hydroxybutyrate ameliorates insulin resistance by inhibiting PPARγ Ser273 phosphorylation in type 2 diabetic mice Zhang, Yudian Li, Zihua Liu, Xinyi Chen, Xinyu Zhang, Shujie Chen, Yuemeng Chen, Jiangnan Chen, Jin Wu, Fuqing Chen, Guo-Qiang Signal Transduct Target Ther Article 3-Hydroxybutyrate (3HB) is a small ketone body molecule produced endogenously by the body in the liver. Previous studies have shown that 3HB can reduce blood glucose level in type 2 diabetic (T2D) patients. However, there is no systematic study and clear mechanism to evaluate and explain the hypoglycemic effect of 3HB. Here we demonstrate that 3HB reduces fasting blood glucose level, improves glucose tolerance, and ameliorates insulin resistance in type 2 diabetic mice through hydroxycarboxylic acid receptor 2 (HCAR2). Mechanistically, 3HB increases intracellular calcium ion (Ca(2+)) levels by activating HCAR2, thereby stimulating adenylate cyclase (AC) to increase cyclic adenosine monophosphate (cAMP) concentration, and then activating protein kinase A (PKA). Activated PKA inhibits Raf1 proto-oncogene serine/threonine-protein kinase (Raf1) activity, resulting in a decrease in extracellular signal-regulated kinases 1/2 (ERK1/2) activity and ultimately inhibiting peroxisome proliferator-activated receptor γ (PPARγ) Ser273 phosphorylation in adipocytes. Inhibition of PPARγ Ser273 phosphorylation by 3HB altered the expression of PPARγ regulated genes and reduced insulin resistance. Collectively, 3HB ameliorates insulin resistance in type 2 diabetic mice through a pathway of HCAR2/Ca(2+)/cAMP/PKA/Raf1/ERK1/2/PPARγ. Nature Publishing Group UK 2023-05-26 /pmc/articles/PMC10212965/ /pubmed/37230992 http://dx.doi.org/10.1038/s41392-023-01415-6 Text en © The Author(s) 2023 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Article
Zhang, Yudian
Li, Zihua
Liu, Xinyi
Chen, Xinyu
Zhang, Shujie
Chen, Yuemeng
Chen, Jiangnan
Chen, Jin
Wu, Fuqing
Chen, Guo-Qiang
3-Hydroxybutyrate ameliorates insulin resistance by inhibiting PPARγ Ser273 phosphorylation in type 2 diabetic mice
title 3-Hydroxybutyrate ameliorates insulin resistance by inhibiting PPARγ Ser273 phosphorylation in type 2 diabetic mice
title_full 3-Hydroxybutyrate ameliorates insulin resistance by inhibiting PPARγ Ser273 phosphorylation in type 2 diabetic mice
title_fullStr 3-Hydroxybutyrate ameliorates insulin resistance by inhibiting PPARγ Ser273 phosphorylation in type 2 diabetic mice
title_full_unstemmed 3-Hydroxybutyrate ameliorates insulin resistance by inhibiting PPARγ Ser273 phosphorylation in type 2 diabetic mice
title_short 3-Hydroxybutyrate ameliorates insulin resistance by inhibiting PPARγ Ser273 phosphorylation in type 2 diabetic mice
title_sort 3-hydroxybutyrate ameliorates insulin resistance by inhibiting pparγ ser273 phosphorylation in type 2 diabetic mice
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10212965/
https://www.ncbi.nlm.nih.gov/pubmed/37230992
http://dx.doi.org/10.1038/s41392-023-01415-6
work_keys_str_mv AT zhangyudian 3hydroxybutyrateamelioratesinsulinresistancebyinhibitingppargser273phosphorylationintype2diabeticmice
AT lizihua 3hydroxybutyrateamelioratesinsulinresistancebyinhibitingppargser273phosphorylationintype2diabeticmice
AT liuxinyi 3hydroxybutyrateamelioratesinsulinresistancebyinhibitingppargser273phosphorylationintype2diabeticmice
AT chenxinyu 3hydroxybutyrateamelioratesinsulinresistancebyinhibitingppargser273phosphorylationintype2diabeticmice
AT zhangshujie 3hydroxybutyrateamelioratesinsulinresistancebyinhibitingppargser273phosphorylationintype2diabeticmice
AT chenyuemeng 3hydroxybutyrateamelioratesinsulinresistancebyinhibitingppargser273phosphorylationintype2diabeticmice
AT chenjiangnan 3hydroxybutyrateamelioratesinsulinresistancebyinhibitingppargser273phosphorylationintype2diabeticmice
AT chenjin 3hydroxybutyrateamelioratesinsulinresistancebyinhibitingppargser273phosphorylationintype2diabeticmice
AT wufuqing 3hydroxybutyrateamelioratesinsulinresistancebyinhibitingppargser273phosphorylationintype2diabeticmice
AT chenguoqiang 3hydroxybutyrateamelioratesinsulinresistancebyinhibitingppargser273phosphorylationintype2diabeticmice