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TMBIM6 is an ER Ca<jats:sup>2+<\/jats:sup> leak channel and its deficiency enhances susceptibility to ER stress due to inhibition of the ER stress sensor IRE1\u03b1. 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<jats:sup>2+<\/jats:sup> regulation in isolated pancreatic \u03b2 cells and increased levels of IRE1\u03b1 levels but no differences in downstream effects of IRE1\u03b1 like increased <jats:italic>Xbp1<\/jats:italic> 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<jats:sup>2+<\/jats:sup> release channel in the ER.<\/jats:p>\n<\/jats:sec><jats:sec>\n<jats:title>Key messages<\/jats:title>\n<jats:p><jats:list list-type=\"bullet\">\n<jats:list-item>\n<jats:p>TMBIM6<jats:sup>\u2212\/\u2212<\/jats:sup> leads to obesity and hepatic steatosis.<\/jats:p>\n<\/jats:list-item>\n<jats:list-item>\n<jats:p>Food intake and energy expenditure are not changed in TMBIM6<jats:sup>\u2212\/\u2212<\/jats:sup> mice.<\/jats:p>\n<\/jats:list-item>\n<jats:list-item>\n<jats:p>No changes in insulin resistance in TMBIM6<jats:sup>\u2212\/\u2212<\/jats:sup> mice.<\/jats:p>\n<\/jats:list-item>\n<jats:list-item>\n<jats:p>Increased insulin secretion caused by altered calcium dynamics in \u03b2 cells.<\/jats:p>\n<\/jats:list-item>\n<\/jats:list><\/jats:p>\n<\/jats:sec>","DOI":"10.1007\/s00109-020-01914-x","type":"journal-article","created":{"date-parts":[[2020,5,11]],"date-time":"2020-05-11T08:03:04Z","timestamp":1589184184000},"page":"849-862","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Bax inhibitor-1 deficiency leads to obesity by increasing Ca2+-dependent insulin secretion"],"prefix":"10.1007","volume":"98","author":[{"given":"Koenraad","family":"Philippaert","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michael","family":"Roden","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dmitrij","family":"Lisak","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Diones","family":"Bueno","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tomas","family":"Jelenik","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Konstantin","family":"Radyushkin","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Teresa","family":"Schacht","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Margot","family":"Mesuere","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Verena","family":"W\u00fcllner","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ann-Kathrin","family":"Herrmann","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jan","family":"Baumgart","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rudi","family":"Vennekens","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8774-0057","authenticated-orcid":false,"given":"Axel","family":"Methner","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2020,5,11]]},"reference":[{"key":"1914_CR1","doi-asserted-by":"publisher","first-page":"89","DOI":"10.1038\/nrm3270","volume":"13","author":"C Hetz","year":"2012","unstructured":"Hetz C (2012) The unfolded protein response: controlling cell fate decisions under ER stress and beyond. 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