Internalization-Dependent Free Fatty Acid Receptor 2 Signaling Is Essential for Propionate-Induced Anorectic Gut Hormone Release

被引：23

作者：

Caengprasath, Natarin ^{[1
]}

Gonzalez-Abuin, Noemi ^{[2
]}

Shchepinova, Maria ^{[3
]}

Ma, Yue ^{[2
]}

Inoue, Asuka ^{[4
]}

Tate, Edward W. ^{[3
]}

Frost, Gary ^{[2
]}

Hanyaloglu, Aylin C. ^{[1
]}

机构：

[1] Imperial Coll London, Dept Metab Digest & Reprod, Inst Reprod & Dev Biol, Rm 2009,Hammersmith Campus,Du Cane Rd, London W12 0NN, England

[2] Imperial Coll London, Dept Metab Digest & Reprod, London, England

[3] Imperial Coll London, Dept Chem, London, England

[4] Tohoku Univ, Grad Sch Pharmaceut Sci, Sendai, Miyagi, Japan

来源：

ISCIENCE | 2020年 / 23卷 / 09期

基金：

英国生物技术与生命科学研究理事会;

关键词：

PEPTIDE-1; SECRETION; FUNCTIONAL-CHARACTERIZATION; ACTIVATION; EXOCYTOSIS; GLP-1; FFA2; MECHANISMS; MICROBIOTA; INHIBITION; INCRETIN;

D O I：

10.1016/j.isci.2020.101449

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

The ability of propionate, a short-chain fatty acid produced from the fermentation of non-digestible carbohydrates in the colon, to stimulate the release of anorectic gut hormones, such as glucagon like peptide-1 (GLP-1), is an attractive approach to enhance appetite regulation, weight management, and glycemic control. Propionate induces GLP-1 release via its G protein-coupled receptor (GPCR), free fatty acid receptor 2 (FFA2), a GPCR that activates Gai and Gaq/11. However, how pleiotropic GPCR signaling mechanisms in the gut regulates appetite is poorly understood. Here, we identify propionate-mediated G protein signaling is spatially directed within the cell whereby FFA2 is targeted to very early endosomes. Furthermore, propionate activates a Gai/p38 signaling pathway, which requires receptor internalization and is essential for propionate-induced GLP-1 release in enteroendocrine cells and colonic crypts. Our study reveals that intestinal metabolites engage membrane trafficking pathways and that receptor internalization could orchestrate complex GPCR pathways within the gut.

引用

页数：34

共 56 条

[1] HIV-1 coreceptor activity of CCR5 and its inhibition by chemokines: Independence from G protein signaling and importance of coreceptor downmodulation [J].

Alkhatib, G ;

Locati, M ;

Kennedy, PE ;

Murphy, PM ;

Berger, EA .

VIROLOGY, 1997, 234 (02) :340-348

[2] FFAR2-FFAR3 receptor heteromerization modulates short-chain fatty acid sensing [J].

Ang, Zhiwei ;

Xiong, Ding ;

Wu, Min ;

Ding, Jeak Ling .

FASEB JOURNAL, 2018, 32 (01) :289-+

[3] ACTIVATION OF EXOCYTOSIS BY THE HETEROTRIMERIC-G PROTEIN-G(I3) [J].

ARIDOR, M ;

RAJMILEVICH, G ;

BEAVEN, MA ;

SAGIEISENBERG, R .

SCIENCE, 1993, 262 (5139) :1569-1572

[4] A Novel Allosteric Activator of Free Fatty Acid 2 Receptor Displays Unique Gi-functional Bias [J].

Bolognini, Daniele ;

Moss, Catherine E. ;

Nilsson, Karolina ;

Petersson, Annika U. ;

Donnelly, Iona ;

Sergeev, Eugenia ;

Koenig, Gabriele M. ;

Kostenis, Evi ;

Kurowska-Stolarska, Mariola ;

Miller, Ashley ;

Dekker, Niek ;

Tobin, Andrew B. ;

Milligan, Graeme .

JOURNAL OF BIOLOGICAL CHEMISTRY, 2016, 291 (36) :18915-18931

[5] The orphan G protein-coupled receptors GPR41 and GPR43 are activated by propionate and other short chain carboxylic acids [J].

Brown, AJ ;

Goldsworthy, SM ;

Barnes, AA ;

Eilert, MM ;

Tcheang, L ;

Daniels, D ;

Muir, AI ;

Wigglesworth, MJ ;

Kinghorn, I ;

Fraser, NJ ;

Pike, NB ;

Strum, JC ;

Steplewski, KM ;

Murdock, PR ;

Holder, JC ;

Marshall, FH ;

Szekeres, PG ;

Wilson, S ;

Ignar, DM ;

Foord, SM ;

Wise, A ;

Dowell, SJ .

JOURNAL OF BIOLOGICAL CHEMISTRY, 2003, 278 (13) :11312-11319

[6] Hardwiring wire-less networks: spatially encoded GPCR signaling in endocrine systems [J].

Caengprasath, Natarin ;

Hanyaloglu, Aylin C. .

CURRENT OPINION IN CELL BIOLOGY, 2019, 57 :77-82

[7] Persistent cAMP-Signals Triggered by Internalized G-Protein-Coupled Receptors [J].

Calebiro, Davide ;

Nikolaev, Viacheslav O. ;

Gagliani, Maria Cristina ;

de Filippis, Tiziana ;

Dees, Christian ;

Tacchetti, Carlo ;

Persani, Luca ;

Lohse, Martin J. .

PLOS BIOLOGY, 2009, 7 (08)

[8] Essential Role of Syntaxin-Binding Protein-1 in the Regulation of Glucagon-Like Peptide-1 Secretion [J].

Campbell, Jhenielle R. ;

Martchenko, Alexandre ;

Sweeney, Maegan E. ;

Maalouf, Michael F. ;

Psichas, Arianna ;

Gribble, Fiona M. ;

Reimann, Frank ;

Brubaker, Patricia L. .

ENDOCRINOLOGY, 2020, 161 (05)

[9] Dietary supplementation with inulin-propionate ester or inulin improves insulin sensitivity in adults with overweight and obesity with distinct effects on the gut microbiota, plasma metabolome and systemic inflammatory responses: a randomised crossover trial [J].

Chambers, Edward S. ;

Byrne, Claire S. ;

Morrison, Douglas J. ;

Murphy, Kevin G. ;

Preston, Tom ;

Tedford, Catriona ;

Garcia-Perez, Isabel ;

Fountana, Sofia ;

Serrano-Contreras, Jose Ivan ;

Holmes, Elaine ;

Reynolds, Catherine J. ;

Roberts, Jordie F. ;

Boyton, Rosemary J. ;

Altmann, Daniel M. ;

McDonald, Julie A. K. ;

Marchesi, Julian R. ;

Akbar, Arne N. ;

Riddell, Natalie E. ;

Wallis, Gareth A. ;

Frost, Gary S. .

GUT, 2019, 68 (08) :1430-1438

[10] Effects of targeted delivery of propionate to the human colon on appetite regulation, body weight maintenance and adiposity in overweight adults [J].

Chambers, Edward S. ;

Viardot, Alexander ;

Psichas, Arianna ;

Morrison, Douglas J. ;

Murphy, Kevin G. ;

Zac-Varghese, Sagen E. K. ;

MacDougall, Kenneth ;

Preston, Tom ;

Tedford, Catriona ;

Finlayson, Graham S. ;

Blundell, John E. ;

Bell, Jimmy D. ;

Thomas, E. Louise ;

Mt-Isa, Shahrul ;

Ashby, Deborah ;

Gibson, Glen R. ;

Kolida, Sofia ;

Dhillo, Waljit S. ;

Bloom, Stephen R. ;

Morley, Wayne ;

Clegg, Stuart ;

Frost, Gary .

GUT, 2015, 64 (11) :1744-1754

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