Discovery of ciliary G protein-coupled receptors regulating pancreatic islet insulin and glucagon secretion

Wu, Chi-Chang; Hilgendorf, Keren I.; Bevacqua, R. J.; Hang, Yan; Demeter, János; Kim, Seung K.; Jackson, Peter K.

doi:10.1101/2020.10.21.349423

Cited by 5 publications

(15 citation statements)

References 43 publications

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“…Furthermore, the effects of Cpd A were lost in gpr120 but not gpr40 KO islets ( Figure 2 ). These findings are in line with previous studies showing an insulinotropic effect of different GPR120 agonists in vitro in isolated rodent islets and insulin-secreting cell lines (INS-1E and BRIN-BD11) [ 22 , [24] , [25] , [26] ]. In contrast, Oh et al.…”

Section: Discussionsupporting

confidence: 92%

“…GPR120 is also reportedly expressed in islet α, β, δ, and γ cells, where its activation mitigates β cell dysfunction [ 20 ] and apoptosis [ 21 ] and modulates islet hormone secretion. GPR120 activation promotes GSIS [ [22] , [23] , [24] , [25] , [26] ], potentiates glucagon secretion [ 26 , 27 ], inhibits GSSS [ 28 ], and stimulates PP secretion [ 29 ].…”

Section: Introductionmentioning

confidence: 99%

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Free fatty acid receptor 4 inhibitory signaling in delta cells regulates islet hormone secretion in mice

Croze¹,

Flisher

Guillaume³

et al. 2021

Molecular Metabolism

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Objective Maintenance of glucose homeostasis requires the precise regulation of hormone secretion from the endocrine pancreas. Free fatty acid receptor 4 (FFAR4/GPR120) is a G protein-coupled receptor whose activation in islets of Langerhans promotes insulin and glucagon secretion and inhibits somatostatin secretion. However, the contribution of individual islet cell types (α, β, and δ cells) to the insulinotropic and glucagonotropic effects of GPR120 remains unclear. As gpr120 mRNA is enriched in somatostatin-secreting δ cells, we hypothesized that GPR120 activation stimulates insulin and glucagon secretion via inhibition of somatostatin release. Methods Glucose tolerance tests were performed in mice after administration of selective GPR120 agonist Compound A. Insulin, glucagon, and somatostatin secretion were measured in static incubations of isolated mouse islets in response to endogenous (ω-3 polyunsaturated fatty acids) and/or pharmacological (Compound A and AZ-13581837) GPR120 agonists. The effect of Compound A on hormone secretion was tested further in islets isolated from mice with global or somatostatin cell-specific knock-out of gpr120 . Gpr120 expression was assessed in pancreatic sections by RNA in situ hybridization. Cyclic AMP (cAMP) and calcium dynamics in response to pharmacological GPR120 agonists were measured specifically in α, β, and δ cells in intact islets using cAMPER and GCaMP6 reporter mice, respectively. Results Acute exposure to Compound A increased glucose tolerance, circulating insulin, and glucagon levels in vivo. Endogenous and/or pharmacological GPR120 agonists reduced somatostatin secretion in isolated islets and concomitantly demonstrated dose-dependent potentiation of glucose-stimulated insulin secretion and arginine-stimulated glucagon secretion. Gpr120 was enriched in δ cells. Pharmacological GPR120 agonists reduced cAMP and calcium levels in δ cells but increased these signals in α and β cells. Compound A-mediated inhibition of somatostatin secretion was insensitive to pertussis toxin. The effect of Compound A on hormone secretion was completely absent in islets from mice with either global or somatostatin cell-specific deletion of gpr120 and partially reduced upon blockade of somatostatin receptor signaling by cyclosomatostatin. Conclusions Inhibitory GPR120 signaling in δ cells contributes to both insulin and glucagon secretion in part by mitigating somatostatin release.

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Section: Discussionsupporting

confidence: 92%

Section: Introductionmentioning

confidence: 99%

Free fatty acid receptor 4 inhibitory signaling in delta cells regulates islet hormone secretion in mice

Croze¹,

Flisher

Guillaume³

et al. 2021

Molecular Metabolism

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“…Mechanistically, any GPR120 expressed by α or β cells is clearly coupled to distinct downstream canonical signaling pathways compared to the inhibition of calcium and cAMP that characterizes GPR120 activation in δ cells. Furthermore, recent studies suggest that GPR120 is localized to primary cilia in mouse and human islet endocrine cells and that disrupting the cilial transport of GPR120 precludes agonist-dependent potentiation of insulin and glucagon secretion [26]. This finding is perfectly compatible with a role for GPR120 in δ cells in the regulation of insulin and glucagon secretion in islets.…”

Section: Discussionsupporting

confidence: 59%

“…This finding is perfectly compatible with a role for GPR120 in δ cells in the regulation of insulin and glucagon secretion in islets. δ cells are also ciliated [26], and disruption of ciliary transport in islets would be expected to interfere with the GPR120-mediated inhibition of SST secretion. In addition, depletion of primary cilia in the β cell prevents SST inhibition of GSIS [44].…”

Section: Discussionmentioning

confidence: 99%

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Free fatty-acid receptor 4 inhibitory signaling in delta cells regulates islet hormone secretion in mice

Croze¹,

Flisher

Guillaume³

et al. 2020

Preprint

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Objective: Maintenance of glucose homeostasis requires the precise regulation of hormone secretion from the endocrine pancreas. Free-fatty acid receptor 4 (FFAR4/Gpr120) is a G protein-coupled receptor whose activation in islets of Langerhans promotes insulin and glucagon secretion and inhibits somatostatin secretion. However, the contribution of individual islet cell types (α, β, and δ cells) to the insulinotropic and glucagonotropic effects of Gpr120 remains unclear. As Gpr120 mRNA is enriched in somatostatin-secreting δ cells, we hypothesized that Gpr120 activation stimulates insulin and glucagon secretion via inhibition of somatostatin release. Methods: Glucose tolerance tests were performed in mice after administration of the selective Gpr120 agonist Cpd A. Gpr120 mRNA levels were assessed in pancreatic section by RNA in situ hybridization. Insulin, glucagon and somatostatin secretion were measured in static incubations of isolated mouse islets in response to endogenous (ω-3 polyunsaturated fatty acids) and pharmacological (Compound A and AZ-13581837) Gpr120 agonists. The effect of Compound A on hormone secretion was tested in islets isolated from mice with global or somatostatin cell-specific knockout (KO) of Gpr120. Calcium and cAMP dynamics in response to pharmacological Gpr120 agonists were measured in islets isolated from α, β, and δ cell-specific GCaMP6 and CAMPER reporter mice, respectively. Results: Acute exposure to Compound A increased glucose tolerance and circulating insulin and glucagon levels in vivo. Both pharmacological and endogenous Gpr120 agonists dose-dependently potentiated glucose-stimulated insulin secretion and arginine-stimulated glucagon secretion and concomitantly reduced somatostatin secretion in isolated islets. The effect of Compound A on hormone secretion was completely absent in islets from mice with either global or somatostatin cell-specific deletion of Gpr120, and was partially reduced upon blockade of somatostatin receptor signaling by cyclosomatostatin. Gpr120 agonists reduced forskolin-stimulated cAMP levels in δ cells, but did not evoke calcium signaling in islet cells. Conclusions: This study supports a key contribution of inhibitory Gpr120-Gαi/o signaling in δ cells in both insulin and glucagon secretion in part via mitigating somatostatin release.

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Targeting lipid GPCRs to treat type 2 diabetes mellitus — progress and challenges

Ghislain

Poitout

2021

Nat Rev Endocrinol

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Discovery of ciliary G protein-coupled receptors regulating pancreatic islet insulin and glucagon secretion

Cited by 5 publications

References 43 publications

Free fatty acid receptor 4 inhibitory signaling in delta cells regulates islet hormone secretion in mice

Free fatty acid receptor 4 inhibitory signaling in delta cells regulates islet hormone secretion in mice

Free fatty-acid receptor 4 inhibitory signaling in delta cells regulates islet hormone secretion in mice

Targeting lipid GPCRs to treat type 2 diabetes mellitus — progress and challenges

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