Transcriptional and Functional Characterization of the G Protein-Coupled Receptor Repertoire of Gastric Somatostatin Cells

Egerod, Kristoffer L.; Engelstoft, Maja S.; Lund, Mari L.; Grunddal, Kaare V.; Zhao, Mirabella; Barir-Jensen, Dominique; Nygaard, Else; Petersen, Natalia; Holst, Jens J.; Schwartz, Thue W.

doi:10.1210/en.2015-1388

Cited by 59 publications

(42 citation statements)

References 63 publications

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“…These results further indicate that the epigenetic control of key regulators of hormone secretion is cell-type specific. Notably, Ins2-Cre and Sst-Cre mice may exhibit induced recombination in nonislet cells, such as in the brain and in the stomach (50,51). Although we demonstrated that the hyposecretion of insulin and the hypersecretion of somatostatin from pancreatic islets aid in maintaining normal glucose homeostasis ( Figure 1H and Figure 2), the deficiencies of CUL4B in SST-synthesized cells other than islets may also contribute to impaired glucose tolerance in Sst-Cre +/-Cul4b fl/Y mice, a possibility that requires further study.…”

Section: Discussionmentioning

confidence: 99%

A cullin 4B-RING E3 ligase complex fine-tunes pancreatic δ cell paracrine interactions

Cui

Yang

et al. 2017

Journal of Clinical Investigation

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Figure 1. CUL4B deficiency in pancreatic δ cells impairs glucose metabolism. (A and B)Western blots and quantitative data for CUL4A and CUL4B protein levels in islets from 12-week-old diabetic db/db mice and their heterozygous littermates (db/+). n = 6 mice per group. Representative Western blots from at least 3 independent experiments are shown. (C) Immunostaining for CUL4B (green) and somatostatin (SST, red) in pancreatic sections from db/db and db/+ mice. Scale bar: 100 μm. n = 6 mice per group; 4-7 random areas were selected from each islet section, and 10 sections were randomly selected from each mouse. Insulininduced decreases in blood glucose levels were significantly lower in Sst-Cre +/-Cul4b fl/Y mice than in their WT littermates, and they did not return to baseline levels at the 2-hour time point, whereas the levels of their WT littermates did (n = 9-11). *P < 0.05; **P < 0.01; ***P < 0.001. db/db mice were compared with their db/+ littermates, and Sst-Cre +/-Cul4b fl/Y mice were compared with their WT littermates. Error bars in F represent mean ± SD; other bars represent mean ± SEM. All data were analyzed using 1-way ANOVA. The Journal of Clinical Investigation R E S E A R C H A R T I C L E2 6 3 3 jci.orgVolume 127 Number 7 July 2017mental Figure 1E). Immunofluorescence also showed no significant differences in islet or β or δ cell numbers between +/-mice, the knockout mice exhibited increased glucose levels after 2 hours of feeding following a 16-hour fast ( Figure 1G). Accordingly, during a glucose tolerance test, the blood glucose levels of Sst-Cre +/-Cul4b fl/Y mice were 33% and 30% higher at 30 minutes and 120 minutes, respectively, than those of the control group consisting of both Sst-Cre +/-and Cul4b fl/Y mice ( Figure 1H). In addition, during the insulin tolerance test, the blood glucose levels of Sst-Cre +/-Cul4b fl/Y mice unexpectedly decreased more dramatically and rapidly than those of the Sst-Cre +/-control mice in response to insulin stimulation ( Figure 1I). Insulin and somatostatin content as well as kidney, brain, heart, liver, and stomach weights were not found to be significantly different between the mice was 140% and 40% higher than that of Sst-Cre +/-mice at 5 minutes and 60 minutes, respectively ( Figure 2H). In contrast to the results found for the Sst-Cre +/-Cul4b fl/Y mice, CUL4B defistrated that CRL4 ubiquitinates WD repeat-containing protein 5 (WDR5), a core subunit of H3K4 methyltransferase complexes, for degradation in the nucleus, thereby promoting increased H3K4 methylation levels (30). However, whether CUL4B or its E3 ligase complex CRL4B-PRC2 participates in the functioning or development of Langerhans islets has not been studied. In this study, we found that CUL4B expression levels are decreased in db/db mice. Therefore, we crossed mice expressing Cre under the insulin II promotor (Ins2-Cre) and mice expressing Cre under the somatostatin promoter (Sst-Cre) with Cul4b fl/fl mice to characterize CUL4B functions in specific cell types of the islet circuit. Although In...

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Section: Discussionmentioning

confidence: 99%

A cullin 4B-RING E3 ligase complex fine-tunes pancreatic δ cell paracrine interactions

Cui

Yang

et al. 2017

Journal of Clinical Investigation

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“…259 This compound inhibited release of ghrelin with micromolar potency, an effect lacking in cells derived from FFA4 knockout mice, and inhibited release of somatostatin from primary mouse gastric mucosal cells. 370 60 ( Figure 27) has been reported as an orally available, small-molecule FFA4 agonist also with high selectivity for FFA4 over FFA1. 325 This compound displayed high potency at human and mouse orthologs of FFA4 in a G q/11 -dependent assay system, while somewhat lower potency was observed in an arrestin 3 interaction assay.…”

Section: Synthetic Ligands For Ffa4mentioning

confidence: 99%

Complex Pharmacology of Free Fatty Acid Receptors

et al. 2016

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G protein-coupled receptors (GPCRs) are historically the most successful family of drug targets. In recent times it has become clear that the pharmacology of these receptors is far more complex than previously imagined. Understanding of the pharmacological regulation of GPCRs now extends beyond simple competitive agonism or antagonism by ligands interacting with the orthosteric binding site of the receptor to incorporate concepts of allosteric agonism, allosteric modulation, signaling bias, constitutive activity, and inverse agonism. Herein, we consider how evolving concepts of GPCR pharmacology have shaped understanding of the complex pharmacology of receptors that recognize and are activated by nonesterified or "free" fatty acids (FFAs). The FFA family of receptors is a recently deorphanized set of GPCRs, the members of which are now receiving substantial interest as novel targets for the treatment of metabolic and inflammatory diseases. Further understanding of the complex pharmacology of these receptors will be critical to unlocking their ultimate therapeutic potential.

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“…12 Moreover, FFA4 is implicated in regulation of glucagon, ghrelin and somatostatin release, representing likely contributing mechanisms of the observed metabolic phenotype. [13][14][15][16] Chart 1. Representative FFA4 agonists…”

Section: Introductionmentioning

confidence: 99%

Non-Acidic Free Fatty Acid Receptor 4 Agonists with Antidiabetic Activity

et al. 2016

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ABSTRACT. The free fatty acid receptor 4 (FFA4 or GPR120) has appeared as an interesting potential target for the treatment of metabolic disorders. At present, most FFA4 ligands are carboxylic acids that are assumed to mimic the endogenous long-chain fatty acid agonists. Here, we report preliminary structure-activity relationship studies of a previously disclosed non-acidic sulfonamide FFA4 agonist. Mutagenesis studies indicate that the compounds are orthosteric agonists despite the absence of a carboxylate function. The preferred compounds showed full agonist activity on FFA4 and complete selectivity over FFA1, although a significant fraction of these non-carboxylic acids also showed partial antagonistic activity on FFA1. Studies in normal and diet-induced obese (DIO) mice with the preferred compound 34 showed improved glucose tolerance after oral dosing in an oral glucose tolerance test. Chronic dosing of 34 in DIO mice resulted in significantly increased insulin sensitivity and a moderate but significant reduction in bodyweight, effects that were also present in mice lacking FFA1 but absent in mice lacking FFA4.

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Transcriptional and Functional Characterization of the G Protein-Coupled Receptor Repertoire of Gastric Somatostatin Cells

Cited by 59 publications

References 63 publications

A cullin 4B-RING E3 ligase complex fine-tunes pancreatic δ cell paracrine interactions

A cullin 4B-RING E3 ligase complex fine-tunes pancreatic δ cell paracrine interactions

Complex Pharmacology of Free Fatty Acid Receptors

Non-Acidic Free Fatty Acid Receptor 4 Agonists with Antidiabetic Activity

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