Autocrine negative feedback regulation of lipolysis through sensing of NEFAs by FFAR4/GPR120 in WAT

Husted, Anna Sofie; Ekberg, Jeppe H.; Tripp, Emma; Nissen, Tinne A. D.; Meijnikman, Stijn; O’Brien, Shannon; Ulven, Trond; Acherman, Yaïr I. Z.; Bruin, Sjoerd C.; Nieuwdorp, Max; Gerhart-Hines, Zachary; Calebiro, Davide; Dragsted, Lars Ove; Schwartz, Thue W.

doi:10.1016/j.molmet.2020.101103

Cited by 19 publications

(20 citation statements)

References 51 publications

(51 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…As GPR120 is known to couple to inhibitory G proteins Gαi/o [ 10 , 13 ], we asked whether the decrease in SST secretion in response to Cpd A can be reversed by pre-treating islets with PTX, an inhibitor of Gαi/o activity ( Figure 8 A). The basal and glucose-induced increase in SST secretion were elevated in islets pretreated with PTX, consistent with Gαi/o inactivation alleviating tonic negative feedback from SST.…”

Section: Resultsmentioning

confidence: 99%

“…Among these, long-chain FA 1 receptor GPR120/FFAR4 has been the subject of increasing interest in recent years as its activation has numerous beneficial effects on glucose and energy homeostasis in preclinical models [ 2 ]. In rodents, GPR120 activation alleviates obesity-induced chronic inflammation and associated insulin resistance [ 3 , 4 ], promotes adipogenesis [ [5] , [6] , [7] ] and brown adipose tissue thermogenesis [ 8 , 9 ], inhibits lipolysis in white adipose tissue [ 10 ], regulates food intake [ 11 ], and modulates enteroendocrine hormone secretion, including ghrelin [ [12] , [13] , [14] ], glucagon-like peptide-1 [ 15 ], glucose-dependent insulinotropic polypeptide [ 16 ], cholecystokinin [ 17 , 18 ], and SST [ 19 ].…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

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

Croze¹,

Flisher

Guillaume³

et al. 2021

Molecular Metabolism

View full text Add to dashboard Cite

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.

show abstract

Section: Resultsmentioning

confidence: 99%

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

View full text Add to dashboard Cite

show abstract

“…As GPR120 is known to couple to inhibitory G proteins Gαi/o [10; 13], we asked whether the decrease in SST secretion in response to Cpd A can be reversed by pre-treating islets with PTX, an inhibitor of Gαi/o activity ( Fig. 8A ).…”

Section: Resultsmentioning

confidence: 99%

“…G protein-coupled receptors are validated targets for the treatment of type 2 diabetes [1] and among these, the long-chain FA 1 receptor GPR120/FFAR4 has been the subject of increasing interest in recent years as its activation has numerous beneficial effects on glucose and energy homeostasis in preclinical models [2]. In rodents, GPR120 activation alleviates obesity-induced chronic inflammation and associated insulin resistance [3; 4], promotes adipogenesis [5][6][7] and brown adipose tissue thermogenesis [8; 9], inhibits lipolysis in white adipose tissue [10], regulates food intake [11], and modulates enteroendocrine hormone secretion, including ghrelin [12][13][14], glucagon-like peptide-1 [15], glucose-dependent insulinotropic polypeptide [16], cholecystokinin [17; 18] and SST [19]. 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.…”

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. 2020

Preprint

View full text Add to dashboard Cite

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.

show abstract

“…This mechanism is dependent on signaling through Gq. However, recent findings indicate that GPR120 can also signal via Gi as part of an autocrine negative feedback mechanism to regulate lipolysis by the released free fatty acids [37].…”

Section: Gpr120mentioning

confidence: 99%

Metabolic responses of light and taste receptors – unexpected actions of GPCRs in adipocytes

Ekechukwu

Christian

2021

Rev Endocr Metab Disord

View full text Add to dashboard Cite

The G-protein-coupled receptor (GPCR) superfamily includes sensory receptors that can detect and respond to taste and light. Recent investigations have identified key metabolic roles for such receptors in tissues considered ‘non-sensory’ such as adipose tissue. The major functions of white and brown adipose tissues include energy storage/release and thermogenesis, respectively. These processes are tightly controlled by GPCR pathways that serve to maintain energy homeostasis. Opsins 3 and 4 are GPCRs activated by blue light and in adipocytes control lipolysis as well as affect brown adipocyte activity. Furthermore, Opsin 3 signals to regulate the conversion of white to thermogenic beige/BRITE (Brown-in-white) adipocytes. Taste receptors that respond to fatty acids, sweet and bitter are expressed in adipocytes as well as in taste buds. Ffar2 and the long chain fatty acid receptor GPR120 are highly expressed in white adipocytes and the human tongue. In adipose tissue Ffar2 mediates the metabolic effects of butyrate and propionate produced by the gut microbiome. GPR120 is highly expressed in brown adipose tissue and regulates fatty acid oxidation and mitochondrial function. The type I taste receptor Tas1r3 senses sweet and umami, is expressed in adipocytes and on obesogenic diets Tas1r3 global gene knockout protects from metabolic dysfunction. Type II taste receptors that sense bitter are expressed by adipocytes and bitter agonists have been found to modulate adipocyte differentiation and lipid storage levels. This review explores recent unexpected findings of light and taste receptors in adipocytes and examines effects of their signaling in the control of adipose tissue biology.

show abstract

Autocrine negative feedback regulation of lipolysis through sensing of NEFAs by FFAR4/GPR120 in WAT

Cited by 19 publications

References 51 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

Metabolic responses of light and taste receptors – unexpected actions of GPCRs in adipocytes

Contact Info

Product

Resources

About