Endosomal free fatty acid receptor 2 signaling is essential for propionate-induced anorectic gut hormone release

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 glycaemic control. Propionate induces GLP-1 release via its G protein-coupled receptor (GPCR), free fatty acid receptor 2 (FFA2); a GPCR that activates Gαi and Gαq/11 pathways. 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 via the targeting of FFA2 to very early endosomes. Furthermore, propionate activates an endosomal Gαi/p38 signaling pathway, which is essential for propionate-induced GLP-1 release in enteroendocrine cells and colonic crypts. Our study reveals that intestinal metabolites can engage membrane trafficking pathways and endosomal signaling platforms to orchestrate complex GPCR pathways within the gut.

[1]  D. Altmann,et al.  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 , 2019 .

[2]  A. Hanyaloglu,et al.  Hardwiring wire-less networks: spatially encoded GPCR signaling in endocrine systems. , 2019, Current opinion in cell biology.

[3]  Haifang Li,et al.  SCFAs-Induced GLP-1 Secretion Links the Regulation of Gut Microbiome on Hepatic Lipogenesis in Chickens , 2019, bioRxiv.

[4]  L. Wood,et al.  Short-chain fatty acids increase TNFα-induced inflammation in primary human lung mesenchymal cells through the activation of p38 MAPK. , 2019, American journal of physiology. Lung cellular and molecular physiology.

[5]  G. Frost,et al.  Short chain fatty acids stimulate insulin secretion and reduce apoptosis in mouse and human islets in vitro: Role of free fatty acid receptor 2 , 2018, Diabetes, obesity & metabolism.

[6]  J. Olefsky,et al.  N-Thiazolylamide-based free fatty-acid 2 receptor agonists: Discovery, lead optimization and demonstration of off-target effect in a diabetes model. , 2018, Bioorganic & medicinal chemistry.

[7]  Alex R. B. Thomsen,et al.  Therapeutic Targeting of Endosomal G-Protein-Coupled Receptors. , 2018, Trends in pharmacological sciences.

[8]  J. Garssen,et al.  The Anti-inflammatory Effects of Short Chain Fatty Acids on Lipopolysaccharide- or Tumor Necrosis Factor α-Stimulated Endothelial Cells via Activation of GPR41/43 and Inhibition of HDACs , 2018, Front. Pharmacol..

[9]  M. von Zastrow,et al.  Subcellular Organization of GPCR Signaling. , 2018, Trends in pharmacological sciences.

[10]  P. Rorsman,et al.  AP2σ Mutations Impair Calcium-Sensing Receptor Trafficking and Signaling, and Show an Endosomal Pathway to Spatially Direct G-Protein Selectivity , 2018, Cell reports.

[11]  J. Wess,et al.  Lack of beta-arrestin signaling in the absence of active G proteins , 2018, Nature Communications.

[12]  J. Brosens,et al.  Integration of GPCR Signaling and Sorting from Very Early Endosomes via Opposing APPL1 Mechanisms , 2017, Cell reports.

[13]  J. L. Ding,et al.  FFAR2-FFAR3 receptor heteromerization modulates short-chain fatty acid sensing , 2017, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[14]  T. Schwartz,et al.  Gq and Gs signaling acting in synergy to control GLP-1 secretion , 2017, Molecular and Cellular Endocrinology.

[15]  T. Jin,et al.  The incretin hormone GLP‐1 and mechanisms underlying its secretion , 2016, Journal of diabetes.

[16]  Ashley M. Miller,et al.  A Novel Allosteric Activator of Free Fatty Acid 2 Receptor Displays Unique Gi-functional Bias* , 2016, The Journal of Biological Chemistry.

[17]  K. Jacobson,et al.  On the selectivity of the Gαq inhibitor UBO-QIC: A comparison with the Gαi inhibitor pertussis toxin. , 2016, Biochemical pharmacology.

[18]  M. von Zastrow,et al.  β-arrestin drives MAP kinase signaling from clathrin-coated structures after GPCR dissociation , 2016, Nature Cell Biology.

[19]  Jiong Shi,et al.  Pertussis toxin reduces calcium influx to protect ischemic stroke in a middle cerebral artery occlusion model , 2015, Journal of neurochemistry.

[20]  F. Bäckhed,et al.  The short-chain fatty acid receptor, FFA2, contributes to gestational glucose homeostasis. , 2015, American journal of physiology. Endocrinology and metabolism.

[21]  Phillip P. Le,et al.  Ubiquitin plays an atypical role in GPCR-induced p38 MAP kinase activation on endosomes , 2015, The Journal of cell biology.

[22]  K. Murphy,et al.  The L-Cell in Nutritional Sensing and the Regulation of Appetite , 2015, Front. Nutr..

[23]  Jimmy D Bell,et al.  Effects of targeted delivery of propionate to the human colon on appetite regulation, body weight maintenance and adiposity in overweight adults , 2014, Gut.

[24]  M. von Zastrow,et al.  Spatial encoding of cyclic AMP signalling specificity by GPCR endocytosis , 2014, Nature chemical biology.

[25]  G. Frost,et al.  The short chain fatty acid propionate stimulates GLP-1 and PYY secretion via free fatty acid receptor 2 in rodents , 2014, International Journal of Obesity.

[26]  A. Hanyaloglu,et al.  Spatially Restricted G Protein-coupled Receptor Activity via Divergent Endocytic Compartments* , 2013, The Journal of Biological Chemistry.

[27]  James A Daniel,et al.  Building a Better Dynasore: The Dyngo Compounds Potently Inhibit Dynamin and Endocytosis , 2013, Traffic.

[28]  Barbara M. Bakker,et al.  The role of short-chain fatty acids in the interplay between diet, gut microbiota, and host energy metabolism , 2013, Journal of Lipid Research.

[29]  Shing-Hwa Liu,et al.  Low molecular weight chitosan accelerates glucagon-like peptide-1 secretion in human intestinal endocrine cells via a p38-dependent pathway. , 2013, Journal of agricultural and food chemistry.

[30]  Graeme Milligan,et al.  Defining the Molecular Basis for the First Potent and Selective Orthosteric Agonists of the FFA2 Free Fatty Acid Receptor* , 2013, The Journal of Biological Chemistry.

[31]  Lee M. Kaplan,et al.  Conserved Shifts in the Gut Microbiota Due to Gastric Bypass Reduce Host Weight and Adiposity , 2013, Science Translational Medicine.

[32]  A. M. Habib,et al.  Short-Chain Fatty Acids Stimulate Glucagon-Like Peptide-1 Secretion via the G-Protein–Coupled Receptor FFAR2 , 2012, Diabetes.

[33]  G. Roman,et al.  Heme Oxygenase Inhibition by 1‐Aryl‐2‐(1H‐imidazol‐1‐yl/1H‐1,2,4‐triazol‐1‐yl)ethanones and Their Derivatives , 2010, ChemMedChem.

[34]  R. Xavier,et al.  Regulation of inflammatory responses by gut microbiota and chemoattractant receptor GPR43 , 2009, Nature.

[35]  Yang Li,et al.  Identification and Functional Characterization of Allosteric Agonists for the G Protein-Coupled Receptor FFA2 , 2008, Molecular Pharmacology.

[36]  K. Thorn,et al.  Real-Time Imaging of Discrete Exocytic Events Mediating Surface Delivery of AMPA Receptors , 2007, The Journal of Neuroscience.

[37]  R. Reimer.  Meat hydrolysate and essential amino acid-induced glucagon-like peptide-1 secretion, in the human NCI-H716 enteroendocrine cell line, is regulated by extracellular signal-regulated kinase1/2 and p38 mitogen-activated protein kinases. , 2006, The Journal of endocrinology.

[38]  M. Taniguchi,et al.  A Novel Gαq/11-selective Inhibitor* , 2004, Journal of Biological Chemistry.

[39]  M. Parmentier,et al.  Functional Characterization of Human Receptors for Short Chain Fatty Acids and Their Role in Polymorphonuclear Cell Activation* , 2003, Journal of Biological Chemistry.

[40]  P. Gibson,et al.  Dietary fibre: a roughage guide , 2003, Internal medicine journal.

[41]  S. Dowell,et al.  The Orphan G Protein-coupled Receptors GPR41 and GPR43 Are Activated by Propionate and Other Short Chain Carboxylic Acids* , 2003, The Journal of Biological Chemistry.

[42]  Jiahuai Han,et al.  MAPKK-Independent Activation of p38α Mediated by TAB1-Dependent Autophosphorylation of p38α , 2002, Science.

[43]  Gero Miesenböck,et al.  Visualizing secretion and synaptic transmission with pH-sensitive green fluorescent proteins , 1998, Nature.

[44]  J. Henquin,et al.  Relative contribution of Ca2+‐dependent and Ca2+‐independent mechanisms to the regulation of insulin secretion by glucose , 1998, FEBS letters.

[45]  M. Locati,et al.  HIV-1 coreceptor activity of CCR5 and its inhibition by chemokines: independence from G protein signaling and importance of coreceptor downmodulation. , 1997, Virology.

[46]  T. Schermerhorn,et al.  Glucose stimulation of insulin release in the absence of extracellular Ca2+ and in the absence of any increase in intracellular Ca2+ in rat pancreatic islets. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[47]  M. Aridor,et al.  Activation of exocytosis by the heterotrimeric G protein Gi3. , 1993, Science.

[48]  M. Marletta,et al.  NG-allyl- and NG-cyclopropyl-L-arginine: two novel inhibitors of macrophage nitric oxide synthase. , 1992, Journal of medicinal chemistry.

[49]  S. Bloom,et al.  GLUCAGON-LIKE PEPTIDE-1 7-36: A PHYSIOLOGICAL INCRETIN IN MAN , 1987, The Lancet.

[50]  A. Bender.  Dietary Fibre , 1977, The Lancet.

[51]  A. Hanyaloglu.  Advances in Membrane Trafficking and Endosomal Signaling of G Protein-Coupled Receptors. , 2018, International review of cell and molecular biology.

[52]  Y. Obara,et al.  Short-chain fatty acids induce acute phosphorylation of the p38 mitogen-activated protein kinase/heat shock protein 27 pathway via GPR43 in the MCF-7 human breast cancer cell line. , 2007, Cellular signalling.

[53]  M. Taniguchi,et al.  A novel Galphaq/11-selective inhibitor. , 2004, The Journal of biological chemistry.

[54]  K. Sullivan,et al.  Regulation of inflammation , 2003, Immunologic research.

[55]  Jiahuai Han,et al.  MAPKK-independent activation of p38alpha mediated by TAB1-dependent autophosphorylation of p38alpha. , 2002, Science.

[56]  C. Edwards,et al.  Short Chain Fatty Acids , 1999 .

[57]  J. Cummings,et al.  Short chain fatty acids , 1994 .