Movatterモバイル変換

[0]ホーム
URL:

Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
Thehttps:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

NIH NLM Logo
Log inShow account info
Access keysNCBI HomepageMyNCBI HomepageMain ContentMain Navigation
pubmed logo
Advanced Clipboard
User Guide

Full text links

Silverchair Information Systems full text link Silverchair Information Systems Free PMC article
Full text links

Actions

.2015 Jul;29(7):1055-66.
doi: 10.1210/me.2015-1007. Epub 2015 Jun 15.

An Acetate-Specific GPCR, FFAR2, Regulates Insulin Secretion

Affiliations

An Acetate-Specific GPCR, FFAR2, Regulates Insulin Secretion

Medha Priyadarshini et al. Mol Endocrinol.2015 Jul.

Erratum in

  • CORRIGENDUM FOR 10.1210/me.2015-1007.
    [No authors listed][No authors listed]Mol Endocrinol. 2016 Jul;30(7):826. doi: 10.1210/me.2016-1079.Mol Endocrinol. 2016.PMID:27363674Free PMC article.No abstract available.

Abstract

G protein-coupled receptors have been well described to contribute to the regulation of glucose-stimulated insulin secretion (GSIS). The short-chain fatty acid-sensing G protein-coupled receptor, free fatty acid receptor 2 (FFAR2), is expressed in pancreatic β-cells, and in rodents, its expression is altered during insulin resistance. Thus, we explored the role of FFAR2 in regulating GSIS. First, assessing the phenotype of wild-type and Ffar2(-/-) mice in vivo, we observed no differences with regard to glucose homeostasis on normal or high-fat diet, with a marginally significant defect in insulin secretion in Ffar2(-/-) mice during hyperglycemic clamps. In ex vivo insulin secretion studies, we observed diminished GSIS from Ffar2(-/-) islets relative to wild-type islets under high-glucose conditions. Further, in the presence of acetate, the primary endogenous ligand for FFAR2, we observed FFAR2-dependent potentiation of GSIS, whereas FFAR2-specific agonists resulted in either potentiation or inhibition of GSIS, which we found to result from selective signaling through either Gαq/11 or Gαi/o, respectively. Lastly, in ex vivo insulin secretion studies of human islets, we observed that acetate and FFAR2 agonists elicited different signaling properties at human FFAR2 than at mouse FFAR2. Taken together, our studies reveal that FFAR2 signaling occurs by divergent G protein pathways that can selectively potentiate or inhibit GSIS in mouse islets. Further, we have identified important differences in the response of mouse and human FFAR2 to selective agonists, and we suggest that these differences warrant consideration in the continued investigation of FFAR2 as a novel type 2 diabetes target.

PubMed Disclaimer

Figures

Figure 1.
Figure 1.
GTT and ITT withFfar2−/− mice on HFD. A, ip and oral glucose (B) administered to overnight-fasted males on HFD at 26 weeks of age. Blood glucose was measured at 0, 15, 30, 60, and 120 minutes. C, Assessment of insulin tolerance in WT andFfar2−/− mice on HFD at 26 weeks of age. For A–C, blood glucose was measured at 0, 15, 30, 60, and 120 minutes (n = 12–23), and circles represent WT, squares representFfar2−/−.
Figure 2.
Figure 2.
Ffar2−/− mice exhibit trend toward decreased insulin secretion during hyperglycemic clamp. GIR (A) and insulin secretion (B) during 1-hour hyperglycemic clamp in WT andFfar2−/− male mice maintained on NC diet (WT, n = 8;Ffar2−/−, n = 9). C, Insulin area under the curve (AUC) during hyperglycemic clamp studies. D, Insulin sensitivity index (M/I index) calculated by GIR (M) divided by the average 30- to 60-minute insulinemia (I). *,P < .05. For B, circles represent WT, squares representFfar2−/−. For A, C, and D, white bars represent WT, black bars representFfar2−/−.
Figure 3.
Figure 3.
FFAR2 signaling contributes to GSIS. A, Insulin secretion in response to increasing glucose concentrations, or 16.7mM glucose + 100nM Exendin-4 in isolated WT andFfar2−/− islets during static insulin secretion assay (n ≥ 3). Insulin secretion is expressed as a percent of total insulin content. B, Total islet insulin content measured after acid ethanol extraction from 25 islets per replicate. Insulin content was normalized to total protein (n = 4). n.s., not significant. C, Insulin secretion from WT andFfar2−/− islets in response to treatment with high glucose (16.7mM) alone or in combination with 1mM acetate (n ≥ 3). D, Insulin secretion from WT andFfar2−/− islets in response to treatment with high glucose (16.7mM) alone or in combination with 100μM SCA14 or 100μM SCA15 (n ≥ 3). E, Insulin secretion from WT andFfar2−/− islets in response to treatment with 16.7mM glucose or in combination with 100μM CMTB or 100μM CPTB (n ≥ 3). F, Insulin secretion from islets obtained from CD-1 mice in response to treatment with 16.7mM glucose or in combination with 1mM acetate, 100μM SCA14, 100μM SCA15, 100μM CMTB, or 100μM CPTB (n ≥ 3). For C–F, values are expressed as a fold change relative to WT islets treated with 16.7mM glucose alone. Asterisks represent significance between genotypes; daggers represent significance within a genotype between the indicated treatment conditions compared with 16.7mM glucose alone. White bars for WT, black bars forFfar2−/−. *,†,P < .05; **,††,P < .01; ***,†††,P < .001; mean ± SEM.
Figure 4.
Figure 4.
FFAR2 differentially regulates GSIS via Gαq/11 and Gαi/o. A, Schematic depicting signaling pathways mediated by FFAR2. B, RT-PCR expression of FFAR2 and FFAR3 in βTC3 cells, β-actin shown as a reference. C, Dose-response curve measuring calcium mobilization in the βTC3 cell line after treatment with acetate at the indicated concentrations. D, Insulin secretion in response to SCA14 and SCA15 after pretreatment with 5μM U73122. E, Insulin secretion in response to CMTB and CPTB after pretreatment with 300-ng/mL PTX. For D and E, insulin secretion is expressed as a fold change relative to WT islets treated with 16.7mM glucose only. Asterisks represent significance between inhibitor treated and untreated islets; daggers represent significance within a condition as compared with 16.7mM glucose alone. For D and E, white bars for untreated, hash bars for inhibitor treated. *,†,P < .05; **,††,P < .01; ***,†††,P < .001; mean ± SEM.
Figure 5.
Figure 5.
Effects of FFAR2 signaling in islets from HFD-fed mice and human islets. A,Ffar2 expression in islets isolated from NC and HFD-fed mice. Expression was measured after 6–8 weeks of HFD and is expressed relative to GAPDH (*,P < .05). B, Insulin secretion from HFD-fed WT andFfar2−/− islets in response to treatment with high glucose (16.7mM) alone or in combination with 1mM acetate or FFAR2-specific agonists (100μM SCA14, 100μM SCA15, 100μM CMTB, or 100μM CPTB). For these insulin secretion experiments, values are expressed as a fold change relative to the high glucose alone condition within each genotype. White bars represent WT, black bars representFfar2−/−. Asterisks represent significance between genotypes; daggers represent significance within a genotype between the indicated treatment conditions compared with 16.7mM glucose alone. C, Insulin secretion from human islets in response to treatment with high glucose (16.7mM) alone or in combination with 1mM acetate or FFAR2-specific agonists (100μM SCA14, 100μM SCA15, 100μM CMTB, or 100μM CPTB) (n = 7). D, Insulin secretion from human islets in response to treatment with high glucose (16.7mM) alone or in combination with 1mM acetate or FFAR2-specific agonists (100μM SCA14, 100μM SCA15, 100μM CMTB, or 100μM CPTB) after pretreatment with 300-ng/mL PTX (n = 5). *,†,P < .05; **,††,P < .01; ***,†††,P < .001; mean ± SEM.
See this image and copyright information in PMC

References

    1. Layden BT, Angueira AR, Brodsky M, Durai V, Lowe WL., Jr Short chain fatty acids and their receptors: new metabolic targets. Transl Res. 2013;161(3):131–140. - PubMed
    1. Johnston CS, Kim CM, Buller AJ. Vinegar improves insulin sensitivity to a high-carbohydrate meal in subjects with insulin resistance or type 2 diabetes. Diabetes Care. 2004;27(1):281–282. - PubMed
    1. Johnston CS, Steplewska I, Long CA, Harris LN, Ryals RH. Examination of the antiglycemic properties of vinegar in healthy adults. Ann Nutr Metab. 2010;56(1):74–79. - PubMed
    1. White AM, Johnston CS. Vinegar ingestion at bedtime moderates waking glucose concentrations in adults with well-controlled type 2 diabetes. Diabetes Care. 2007;30(11):2814–2815. - PubMed
    1. Kondo T, Kishi M, Fushimi T, Ugajin S, Kaga T. Vinegar intake reduces body weight, body fat mass, and serum triglyceride levels in obese Japanese subjects. Biosci Biotechnol Biochem. 2009;73(8):1837–1843. - PubMed

Publication types

MeSH terms

Substances

Grants and funding

LinkOut - more resources

Full text links
Silverchair Information Systems full text link Silverchair Information Systems Free PMC article
Cite
Send To

NCBI Literature Resources

MeSHPMCBookshelfDisclaimer

The PubMed wordmark and PubMed logo are registered trademarks of the U.S. Department of Health and Human Services (HHS). Unauthorized use of these marks is strictly prohibited.

[8]ページ先頭
©2009-2025 Movatter.jp