Dataset Information

Stromal Interaction Molecule 1 Maintains Beta Cell Identity and Function in Female Mice through Preservation of G Protein-Coupled Estrogen Receptor 1 Signaling

ABSTRACT: Loss of pancreatic Beta cell mass, identity, and function contribute to the development of diabetes. Here, we show that the endoplasmic reticulum (ER) calcium sensor, stromal interaction molecule 1 (STIM1), is critical for the maintenance of Beta cell function in female mice. When mice with Beta cell- specific deletion of STIM1 (STIM1-delta-Beta) were challenged with high-fat diet, Beta cell dysfunction was observed in female, but not male, mice. Impaired glucose tolerance was accompanied by reductions in Beta cell mass, a concomitant increase in alpha cell mass, and significant reductions in the expression of markers of Beta cell maturity, including MafA and UCN3. Mechanistic assays demonstrated that the sexually dimorphic phenotype observed in STIM1-Delta-Beta mice was due in part to loss of signaling through the noncanonical 17-Beta estradiol receptor, GPER1. Together, these data suggest that STIM1 orchestrates pancreatic Beta cell function and identity through GPER1- mediated estradiol signaling.

INSTRUMENT(S): Orbitrap Eclipse

ORGANISM(S): Rattus Norvegicus (ncbitaxon:10116)

SUBMITTER: Amber Mosley Carmella Evans-Molina

PROVIDER: MSV000089927 | MassIVE | Wed Jul 20 08:46:00 BST 2022

SECONDARY ACCESSION(S): PXD035461

REPOSITORIES: MassIVE

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Stromal Interaction Molecule 1 Maintains β-Cell Identity and Function in Female Mice Through Preservation of G-Protein-Coupled Estrogen Receptor 1 Signaling.

Sohn Paul P McLaughlin Madeline R MR Krishnan Preethi P Wu Wenting W Slak Rupnik Marjan M Takasu Akira A Senda Toshiya T Lee Chih-Chun CC Kono Tatsuyoshi T Evans-Molina Carmella C

Diabetes 20231001 10

Altered endoplasmic reticulum (ER) Ca2+ signaling has been linked with β-cell dysfunction and diabetes development. Store-operated Ca2+ entry replenishes ER Ca2+ through reversible gating of plasma membrane Ca2+ channels by the ER Ca2+ sensor, stromal interaction molecule 1 (STIM1). For characterization of the in vivo impact of STIM1 loss, mice with β-cell-specific STIM1 deletion (STIM1Δβ mice) were generated and challenged with high-fat diet. Interestingly, β-cell dysfunction was observed in fe ...[more]

PMID: 37478155

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Project description:STIM1 is an endoplasmic reticulum (ER) calcium (Ca2+) sensor that serves to replenish ER Ca2+ stores in response to ER Ca2+ depletion through gating of plasmalemmal Orai1 channels in a process known as store operated calcium entry (SOCE). Previously, we have shown that SOCE is impaired in the diabetic pancreatic β cell; however, the consequences of reduced β cell SOCE have not been well studied. To test this, we generated mice with pancreatic β cell specific deletion of STIM1 (STIM1Δβ). Our results revealed a striking sexual dimorphism in metabolic phenotypes when STIM1Δβ mice were challenged with high fat diet for 8 weeks. Male STIM1Δβ mice showed no differences in total weight, lean or fat mass, or glucose tolerance compared to WT littermate controls. In contrast, female STIM1Δβ mice displayed significantly increased total body weight, fat mass, and reduced glucose tolerance, in vivo glucose-stimulated insulin secretion and β cell mass compared to WT littermate controls, while insulin sensitivity, food intake, and energy expenditure were unchanged. To investigate mechanisms underlying these findings, RNA sequencing was performed in isolated islets and revealed altered 17-beta estradiol (E2) signaling, lipid metabolism, epithelial cell differentiation and decreased noncanonical estradiol receptor GPER. Consistent with this, alpha cell mass was increased in female STIM1Δβ, while proteomics and immunoblot analysis of STIM1 knockout (STIM1KO) INS-1 beta cells revealed reduce insulin expression and increased glucagon expression, suggesting STIM1 may be required for the maintenance of β cell identity. To this end, we show that a reduction of a noncanonical estradiol receptor GPER in STIM1 deficient islets contributes to the marked sexual dimorphism observed during beta cell dysfunction in female STIM1Δβ mice. This present study delineates a sexually dimorphic regulation of STIM1 in the maintenance of pancreatic beta cell identity through GPER and may expand the field of therapeutic approaches to diabetes. Our findings demonstrate the importance of STIM1 and GPER expression stability in the anti-diabetogenic response from estradiol.