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Reininger, L.

Publications and source records attributed to Reininger, L..

3 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↗
bioRxiv2026

Fatty acids from adipocyte lipolysis stimulate insulin secretion

White adipose tissue and pancreatic islets play central roles in the regulation of metabolic homeostasis. Although ectopic lipid accumulation is established as a driver of impaired insulin secretion, the acute contribution of adipocyte lipolysis to islet function remains poorly documented. Here, we investigated a mouse model with inducible adipocyte-specific deletion of both adipose triglyceride lipase (ATGL) and hormone-sensitive lipase (HSL), which leads to defective adipocyte lipolysis. Despite preserved ex vivo islet function, these mice displayed a marked reduction in insulin secretion in response to stimulation of adipocyte {beta}3-adrenoceptors, as well as following glucose and arginine challenges. Mechanistically, we identified non-esterified fatty acids as critical mediators of lipolysis-driven insulin secretion, engaging pancreatic signaling of the free fatty acid receptors FFAR4 (a.k.a. GPR120) and FFAR1 (a.k.a. GPR40). The regulation of insulin secretion by adipocyte lipolysis was preserved in high-fat diet-induced obesity. These findings identify an underappreciated adipose-islet crosstalk that couples adipocyte lipolysis to insulin secretion and links lipid and glucose metabolism.

physiology↗
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↗