Biology subjects

Ethier, M.

Publications and source records attributed to Ethier, M..

5 recordsLinked to original sources

bioRxiv2026

The regulator of G protein signaling RGS9 supports insulin secretion in male mouse islets

Objectives Regulators of G protein signaling (RGS) proteins terminate G protein-coupled receptor signaling and regulate multiple aspects of pancreatic islet function. Although RGS9 is highly enriched in human and rodent islets, its cellular localization and physiological role remain largely unknown. Here, we investigated the expression of Rgs9 in mouse islets and its contribution to insulin secretion. Methods Rgs9 expression was characterized by RNA in situ hybridization and fluorescence-activated cell sorting coupled with quantitative PCR. Rgs9 function was investigated by shRNA-mediated knockdown in wild-type and Dishevelled, Egl-10 and Pleckstrin (DEP) domain-deficient Rgs9 mutant (Rgs9{Delta}DEP/{Delta}DEP) mouse pseudo-islets. Results Rgs9 was detected throughout the endocrine pancreas but was enriched in {beta} and {delta}cells, with the Rgs9-1 isoform representing the predominant splice variant in mouse islets. Rgs9 knockdown in mouse pseudo-islets impaired glucose- and KCl-stimulated insulin secretion without affecting insulin content. In contrast, Rgs9{Delta}DEP/{Delta}DEP mouse islets failed to reproduce this phenotype. Further characterization of the mutant mice revealed persistent expression of Rgs9 transcripts, which when knocked down impaired both glucose- and KCl-stimulated insulin secretion. Conclusions These data indicate that RGS9 supports glucose-stimulated insulin secretion. Given that RGS9 acts exclusively on Gi/o, our results further suggest that RGS9 in {beta} cells dampens inhibitory signaling to promote insulin secretion. Finally, the Rgs9{Delta}DEP/{Delta}DEP mutant does not represent a complete loss-of-function in islets likely due to the retention of the GTPase-activating protein (GAP) activity in the absence of the DEP domain.

cell biology↗

bioRxiv2025

Free fatty acid receptor 4 agonists stimulate insulin secretion via different mechanisms in mouse versus human islets

The free fatty acid receptor FFAR4 is expressed in pancreatic islets, and its activation potentiates insulin and inhibits somatostatin (SST) secretion. We investigated the mechanisms of action of FFAR4 on hormone secretion in mouse and human islets. The effects of the FFAR4 agonist Compound A (Cpd A) on insulin and SST secretion were investigated in islets from mice following ablation of {delta} cells, deletion of SST and deletion of the G protein Gz (Gnaz-/-), in purified mouse {beta} and {delta} cells, in human EndoC-{beta}H5 cells, and in human islets. Ca++ dynamics in response to Cpd A were measured in {delta} cells from Gnaz-/- mouse islets and in human islets. The insulinotropic effect of Cpd A was lost in {delta} cell-ablated and SST-deficient mouse islets and was absent in purified mouse {beta} cells. Gz deletion prevented Cpd A inhibition of SST secretion but not the potentiation of insulin release. Cpd A diminished Ca++ transients in mouse {delta} cells, an effect that was lost in Gz deficient islets. In human islets, FFAR4 activation increased insulin secretion and intracellular Ca++ transient independent of SST secretion. Consistent with a direct effect on {beta} cells, Cpd A potentiated insulin secretion in human EndoC-{beta}H5 cells. We conclude that FFAR4 activation stimulates insulin secretion from mouse islets indirectly via Gz-coupled inhibition of SST secretion from {delta} cells, while in human islets, it stimulates insulin release via a direct effect on {beta} cells. These key species-related differences are to be taken into account as FFAR4 is considered a potential therapeutic target for metabolic diseases. STRUCTURED ABSTRACTO_ST_ABSObjectivesC_ST_ABSThe free fatty acid receptor FFAR4 (GPR120) is expressed in the murine islet where its activation promotes insulin and glucagon and inhibits somatostatin (SST) secretion. However, its precise mechanism of action in different islet cells is still unknown, and potential species-related differences have not been explored. This study was aimed to address three questions: 1-What is the relative importance of {delta} cells and SST in the insulinotropic effect of FFAR4 in mouse islets? 2-Which G protein does FFAR4 couple to in mouse {delta} cells? 3-Does FFAR4 stimulate insulin secretion by similar mechanisms in mouse and human islets? MethodsThe effects of the FFAR4 agonist Compound A (Cpd A) on insulin and SST secretion were investigated in islets from mice following ablation of {delta} cells, deletion of SST and deletion of the G protein Gz (Gnaz-/-), in purified mouse {beta} and {delta} cells, in human EndoC-{beta}H5 cells, and in human islets. Ca++ dynamics in response to Cpd A were measured in {delta} cells from Gnaz-/- mouse islets and in human islets using adenovirally-transduced Ca++ reporters. ResultsThe insulinotropic effect of Cpd A was lost in {delta} cell-ablated and SST-deficient mouse islets and was absent in purified mouse {beta} cells. Gz deletion diminished Ca++ transients in mouse {delta} cells, prevented Cpd A inhibition of SST secretion but did not inhibit the potentiation of insulin release. In human islets, FFAR4 activation increased insulin secretion and intracellular Ca++ transient without affecting SST secretion. Consistent with a direct effect on {beta} cells, Cpd A potentiated insulin secretion in human EndoC-{beta}H5 cells. ConclusionFFAR4 activation stimulates insulin secretion from mouse islets indirectly via Gz-coupled inhibition of SST secretion from {delta} cells, while in human islets, it stimulates insulin release via a direct effect on {beta} cells. These key species-related differences are to be taken into account as FFAR4 is considered a potential therapeutic target for metabolic diseases.

cell biology↗

bioRxiv2022

Beta-cell mass expansion during puberty involves serotonin signaling and determines glucose homeostasis in adulthood

Puberty is associated with transient insulin resistance that normally recedes at the end of puberty; however, in overweight children insulin resistance persists leading to an increased risk of type 2 diabetes. The mechanisms whereby pancreatic {beta} cells adapt to pubertal insulin resistance, and how they are affected by the metabolic status, have not been investigated. Here we show that puberty is associated with a transient increase in {beta}-cell proliferation in rats and humans of both sexes. In rats, {beta}-cell proliferation correlated with a rise in growth hormone (GH) levels. Serum from pubertal rats and humans promoted {beta}-cell proliferation, suggesting the implication of a circulating factor. In pubertal rat islets, expression of genes of the GH/serotonin (5-HT) pathway underwent changes consistent with proliferative effect. Inhibition of the pro-proliferative 5-HT receptor isoform HTR2b blocked the increase in {beta}-cell proliferation in pubertal islets ex vivo and in vivo. Peri-pubertal metabolic stress blunted {beta}-cell proliferation during puberty and led to altered glucose homeostasis later in life. This study identifies a role of GH/GHR/5-HT/HTR2b signaling in the control of {beta}-cell mass expansion during puberty and a mechanistic link between pubertal obesity and the risk of developing type 2 diabetes.

physiology↗

bioRxiv2020

FFAR1 and FFAR4 additively cooperate to control glucose tolerance and insulin secretion in male mice

The free fatty-acid receptors FFAR1 (GPR40) and FFAR4 (GPR120) are implicated in the regulation of insulin secretion and insulin sensitivity, respectively. Although GPR120 and GPR40 share similar ligands, few studies have addressed possible interactions between these two receptors in the control of glucose homeostasis. Here we generated mice deficient in gpr120 (Gpr120KO) or gpr40 (Gpr40KO), alone or in combination (Gpr120/40KO), and metabolically phenotyped male and female mice fed a normal chow or high-fat diet. We assessed insulin secretion in isolated mouse islets exposed to selective GPR120 and GPR40 agonists singly or in combination. Following normal chow feeding, body weight and energy intake were unaffected by deletion of either receptor, although fat mass increased in Gpr120KO females. Fasting blood glucose levels were mildly increased in Gpr120/40KO mice, and in a sex-dependent manner in Gpr120KO and Gpr40KO animals. Oral glucose tolerance was slightly reduced in male Gpr120/40KO mice and in Gpr120KO females, whereas insulin secretion and insulin sensitivity were unaffected. In hyperglycemic clamps, the glucose infusion rate was lower in male Gpr120/40KO mice but insulin and c-peptide levels were unaffected. No changes in glucose tolerance were observed in either single or double KO animals under high-fat feeding. In isolated islets from wild-type mice, the combination of selective GPR120 and GPR40 agonists additively increased insulin secretion. We conclude that while simultaneous activation of GPR120 and GPR40 enhances insulin secretion ex vivo, combined deletion of these two receptors only minimally affects glucose homeostasis in vivo in mice.

physiology↗

bioRxiv2019

HB-EGF Signaling is Required for Glucose-Induced Pancreatic β-Cell Proliferation in Rats

The molecular mechanisms of {beta}-cell compensation to metabolic stress are poorly understood. We previously observed that nutrient-induced {beta}-cell proliferation in rats is dependent on Epidermal Growth Factor Receptor (EGFR) signaling. The aim of this study was to determine the role of the EGFR ligand Heparin-Binding EGF-like Growth Factor (HB-EGF) in the {beta}-cell proliferative response to glucose, a {beta}-cell mitogen and key regulator of {beta}-cell mass in response to increased insulin demand. We show that exposure of isolated rat and human islets to HB-EGF stimulates {beta}-cell proliferation. In rat islets, inhibition of EGFR or HB-EGF blocks the proliferative response not only to HB-EGF but also to glucose. Furthermore, knockdown of HB-EGF in rat islets blocks {beta}-cell proliferation in response to glucose ex vivo and in vivo in transplanted glucose-infused rats. Mechanistically, we demonstrate that HB-EGF mRNA levels are increased in {beta} cells in response to glucose in a Carbohydrate Response Element Binding Protein (ChREBP)-dependent manner. In addition, chromatin-immunoprecipitation studies identified ChREBP binding sites in proximity to the HB-EGF gene. Finally, inhibition of Src family kinases, known to be involved in HB-EGF processing, abrogated glucose-induced {beta}-cell proliferation. Our findings identify a novel glucose/HB-EGF/EGFR axis implicated in {beta}-cell compensation to increased metabolic demand.

cell biology↗