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Bax inhibitor-1 deficiency leads to obesity by increasing Ca(2+)-dependent insulin secretion
ABSTRACT: Transmembrane BAX inhibitor motif containing 6 (TMBIM6), also known as Bax inhibitor-1, is an evolutionarily conserved protein involved in endoplasmic reticulum (ER) function. TMBIM6 is an ER Ca(2+) leak channel and its deficiency enhances susceptibility to ER stress due to inhibition of t...
Autores principales: | , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Springer Berlin Heidelberg
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7297831/ https://www.ncbi.nlm.nih.gov/pubmed/32394396 http://dx.doi.org/10.1007/s00109-020-01914-x |
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author | Philippaert, Koenraad Roden, Michael Lisak, Dmitrij Bueno, Diones Jelenik, Tomas Radyushkin, Konstantin Schacht, Teresa Mesuere, Margot Wüllner, Verena Herrmann, Ann-Kathrin Baumgart, Jan Vennekens, Rudi Methner, Axel |
author_facet | Philippaert, Koenraad Roden, Michael Lisak, Dmitrij Bueno, Diones Jelenik, Tomas Radyushkin, Konstantin Schacht, Teresa Mesuere, Margot Wüllner, Verena Herrmann, Ann-Kathrin Baumgart, Jan Vennekens, Rudi Methner, Axel |
author_sort | Philippaert, Koenraad |
collection | PubMed |
description | ABSTRACT: Transmembrane BAX inhibitor motif containing 6 (TMBIM6), also known as Bax inhibitor-1, is an evolutionarily conserved protein involved in endoplasmic reticulum (ER) function. TMBIM6 is an ER Ca(2+) leak channel and its deficiency enhances susceptibility to ER stress due to inhibition of the ER stress sensor IRE1α. It was previously shown that TMBIM6 overexpression improves glucose metabolism and that TMBIM6 knockout mice develop obesity. We here examined the metabolic alterations underlying the obese phenotype and subjected TMBIM6 knockout mice to indirect calorimetry and euglycemic-hyperinsulinemic tests with stable isotope dilution to gauge tissue-specific insulin sensitivity. This demonstrated no changes in heat production, food intake, activity or hepatic and peripheral insulin sensitivity. TMBIM6 knockout mice, however, featured a higher glucose-stimulated insulin secretion in vivo as assessed by the hyperglycemic clamp test and hepatic steatosis. This coincided with profound changes in glucose-mediated Ca(2+) regulation in isolated pancreatic β cells and increased levels of IRE1α levels but no differences in downstream effects of IRE1α like increased Xbp1 mRNA splicing or Ire1-dependent decay of insulin mRNA in the pancreas. We therefore conclude that lack of TMBIM6 does not affect insulin sensitivity but leads to hyperinsulinemia, which serves to explain the weight gain. TMBIM6-mediated metabolic alterations are mainly caused by its role as a Ca(2+) release channel in the ER. KEY MESSAGES: TMBIM6(−/−) leads to obesity and hepatic steatosis. Food intake and energy expenditure are not changed in TMBIM6(−/−) mice. No changes in insulin resistance in TMBIM6(−/−) mice. Increased insulin secretion caused by altered calcium dynamics in β cells. |
format | Online Article Text |
id | pubmed-7297831 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | Springer Berlin Heidelberg |
record_format | MEDLINE/PubMed |
spelling | pubmed-72978312020-06-19 Bax inhibitor-1 deficiency leads to obesity by increasing Ca(2+)-dependent insulin secretion Philippaert, Koenraad Roden, Michael Lisak, Dmitrij Bueno, Diones Jelenik, Tomas Radyushkin, Konstantin Schacht, Teresa Mesuere, Margot Wüllner, Verena Herrmann, Ann-Kathrin Baumgart, Jan Vennekens, Rudi Methner, Axel J Mol Med (Berl) Original Article ABSTRACT: Transmembrane BAX inhibitor motif containing 6 (TMBIM6), also known as Bax inhibitor-1, is an evolutionarily conserved protein involved in endoplasmic reticulum (ER) function. TMBIM6 is an ER Ca(2+) leak channel and its deficiency enhances susceptibility to ER stress due to inhibition of the ER stress sensor IRE1α. It was previously shown that TMBIM6 overexpression improves glucose metabolism and that TMBIM6 knockout mice develop obesity. We here examined the metabolic alterations underlying the obese phenotype and subjected TMBIM6 knockout mice to indirect calorimetry and euglycemic-hyperinsulinemic tests with stable isotope dilution to gauge tissue-specific insulin sensitivity. This demonstrated no changes in heat production, food intake, activity or hepatic and peripheral insulin sensitivity. TMBIM6 knockout mice, however, featured a higher glucose-stimulated insulin secretion in vivo as assessed by the hyperglycemic clamp test and hepatic steatosis. This coincided with profound changes in glucose-mediated Ca(2+) regulation in isolated pancreatic β cells and increased levels of IRE1α levels but no differences in downstream effects of IRE1α like increased Xbp1 mRNA splicing or Ire1-dependent decay of insulin mRNA in the pancreas. We therefore conclude that lack of TMBIM6 does not affect insulin sensitivity but leads to hyperinsulinemia, which serves to explain the weight gain. TMBIM6-mediated metabolic alterations are mainly caused by its role as a Ca(2+) release channel in the ER. KEY MESSAGES: TMBIM6(−/−) leads to obesity and hepatic steatosis. Food intake and energy expenditure are not changed in TMBIM6(−/−) mice. No changes in insulin resistance in TMBIM6(−/−) mice. Increased insulin secretion caused by altered calcium dynamics in β cells. Springer Berlin Heidelberg 2020-05-11 2020 /pmc/articles/PMC7297831/ /pubmed/32394396 http://dx.doi.org/10.1007/s00109-020-01914-x Text en © The Author(s) 2020 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 licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence 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 licence, visit http://creativecommons.org/licenses/by/4.0/. |
spellingShingle | Original Article Philippaert, Koenraad Roden, Michael Lisak, Dmitrij Bueno, Diones Jelenik, Tomas Radyushkin, Konstantin Schacht, Teresa Mesuere, Margot Wüllner, Verena Herrmann, Ann-Kathrin Baumgart, Jan Vennekens, Rudi Methner, Axel Bax inhibitor-1 deficiency leads to obesity by increasing Ca(2+)-dependent insulin secretion |
title | Bax inhibitor-1 deficiency leads to obesity by increasing Ca(2+)-dependent insulin secretion |
title_full | Bax inhibitor-1 deficiency leads to obesity by increasing Ca(2+)-dependent insulin secretion |
title_fullStr | Bax inhibitor-1 deficiency leads to obesity by increasing Ca(2+)-dependent insulin secretion |
title_full_unstemmed | Bax inhibitor-1 deficiency leads to obesity by increasing Ca(2+)-dependent insulin secretion |
title_short | Bax inhibitor-1 deficiency leads to obesity by increasing Ca(2+)-dependent insulin secretion |
title_sort | bax inhibitor-1 deficiency leads to obesity by increasing ca(2+)-dependent insulin secretion |
topic | Original Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7297831/ https://www.ncbi.nlm.nih.gov/pubmed/32394396 http://dx.doi.org/10.1007/s00109-020-01914-x |
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