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 Ca2+ 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 Ca2+ 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 Ca2+ release channel in the ER.Key messagesTMBIM6−/− 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.
Highlights
The endoplasmic reticulum (ER) is key to the synthesis, folding and sorting of proteins destined for the secretory pathway
We previously reported that adult transmembrane BAX inhibitor motif containing 6 (TMBIM6)−/− (KO) mice kept on normal diet are significantly more obese than their wild-type littermates (Fig. 1a) but did not study this in more detail because we were focusing on changes observed in the immune system [16]
We further focused on inositol-requiring protein 1α (IRE1α), as it was the end of the clamp. g Glucose fluxes calculated from D-[6,6-2H2] glucose dilution during basal and insulin-stimulated conditions. h Percent suppression of endogenous glucose production (EGP) by insulin compared to basal conditions. i Percent stimulation of Rd by insulin compared to basal conditions
Summary
The endoplasmic reticulum (ER) is key to the synthesis, folding and sorting of proteins destined for the secretory pathway. The ER stores and controls intracellular calcium (Ca2+) for a vast array of cellular functions ranging from short-term responses such as contraction and secretion to long-term regulation of cell growth and proliferation [5] Another evolutionarily conserved protein, transmembrane BAX inhibitor motif containing 6 (TMBIM6), known as Bax inhibitor-1 (BI-1), bridges Ca2+ homeostasis and UPR function of the ER [6]. TMBIM6 is a very hydrophobic protein exerting its anti-apoptotic function mainly in paradigms of ER stress but not against stimulators of mitochondrial or TNF/Fas-death receptor apoptosis pathways [7] It is the founding member of a family of six evolutionarily conserved proteins located in diverse intracellular membranes [8]. This highly conserved C-terminus of TMBIM6 [8] forms a Ca2+ pore, which is sufficient to induce Ca2+ leakage from the ER in vitro [12] mediated via a di-aspartyl pH sensor [13, 14], a fact recently corroborated by structural data obtained with a prokaryotic BI-1 ortholog [15]
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