Chemogenetics defines receptor-mediated functions of short chain free fatty acids
Differentiating actions of short chain fatty acids (SCFAs) at free fatty acid receptor 2 (FFA2) from other free fatty acid-responsive receptors and from non-receptor-mediated effects has been challenging. Using a novel chemogenetic and knock-in strategy, whereby an engineered variant of FFA2 (FFA2-DREADD) that is unresponsive to natural SCFAs but is instead activated by sorbic acid replaced the wild-type receptor, we determined that activation of FFA2 in differentiated adipocytes and colonic crypt enteroendocrine cells of mouse accounts fully for SCFA-regulated lipolysis and release of the incretin glucagon-like peptide-1 (GLP-1), respectively. In vivo studies confirmed the specific role of FFA2 in GLP-1 release and also demonstrated a direct role for FFA2 in accelerating gut transit. Thereby, we establish the general principle that such a chemogenetic knock-in strategy can successfully define novel G-protein-coupled receptor (GPCR) biology and provide both target validation and establish therapeutic potential of a 'hard to target' GPCR.
| Medienart: |
E-Artikel |
|---|
| Erscheinungsjahr: |
2019 |
|---|---|
| Erschienen: |
2019 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:15 |
|---|---|
| Enthalten in: |
Nature chemical biology - 15(2019), 5 vom: 16. Mai, Seite 489-498 |
| Sprache: |
Englisch |
|---|
| Beteiligte Personen: |
Bolognini, Daniele [VerfasserIn] |
|---|
| Links: |
|---|
| Themen: |
FFA2R protein, human |
|---|
| Anmerkungen: |
Date Completed 29.07.2019 Date Revised 08.10.2021 published: Print-Electronic Citation Status MEDLINE |
|---|
| doi: |
10.1038/s41589-019-0270-1 |
|---|
| funding: |
|
|---|---|
| Förderinstitution / Projekttitel: |
|
| PPN (Katalog-ID): |
NLM296132616 |
|---|
| LEADER | 01000naa a22002652 4500 | ||
|---|---|---|---|
| 001 | NLM296132616 | ||
| 003 | DE-627 | ||
| 005 | 20231225085157.0 | ||
| 007 | cr uuu---uuuuu | ||
| 008 | 231225s2019 xx |||||o 00| ||eng c | ||
| 024 | 7 | |a 10.1038/s41589-019-0270-1 |2 doi | |
| 028 | 5 | 2 | |a pubmed24n0987.xml |
| 035 | |a (DE-627)NLM296132616 | ||
| 035 | |a (NLM)30992568 | ||
| 040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
| 041 | |a eng | ||
| 100 | 1 | |a Bolognini, Daniele |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Chemogenetics defines receptor-mediated functions of short chain free fatty acids |
| 264 | 1 | |c 2019 | |
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a ƒaComputermedien |b c |2 rdamedia | ||
| 338 | |a ƒa Online-Ressource |b cr |2 rdacarrier | ||
| 500 | |a Date Completed 29.07.2019 | ||
| 500 | |a Date Revised 08.10.2021 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a Differentiating actions of short chain fatty acids (SCFAs) at free fatty acid receptor 2 (FFA2) from other free fatty acid-responsive receptors and from non-receptor-mediated effects has been challenging. Using a novel chemogenetic and knock-in strategy, whereby an engineered variant of FFA2 (FFA2-DREADD) that is unresponsive to natural SCFAs but is instead activated by sorbic acid replaced the wild-type receptor, we determined that activation of FFA2 in differentiated adipocytes and colonic crypt enteroendocrine cells of mouse accounts fully for SCFA-regulated lipolysis and release of the incretin glucagon-like peptide-1 (GLP-1), respectively. In vivo studies confirmed the specific role of FFA2 in GLP-1 release and also demonstrated a direct role for FFA2 in accelerating gut transit. Thereby, we establish the general principle that such a chemogenetic knock-in strategy can successfully define novel G-protein-coupled receptor (GPCR) biology and provide both target validation and establish therapeutic potential of a 'hard to target' GPCR | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 7 | |a FFA2R protein, human |2 NLM | |
| 650 | 7 | |a Fatty Acids, Volatile |2 NLM | |
| 650 | 7 | |a Receptors, Cell Surface |2 NLM | |
| 650 | 7 | |a Receptors, G-Protein-Coupled |2 NLM | |
| 650 | 7 | |a free fatty acid 2 receptor, mouse |2 NLM | |
| 700 | 1 | |a Barki, Natasja |e verfasserin |4 aut | |
| 700 | 1 | |a Butcher, Adrian J |e verfasserin |4 aut | |
| 700 | 1 | |a Hudson, Brian D |e verfasserin |4 aut | |
| 700 | 1 | |a Sergeev, Eugenia |e verfasserin |4 aut | |
| 700 | 1 | |a Molloy, Colin |e verfasserin |4 aut | |
| 700 | 1 | |a Moss, Catherine E |e verfasserin |4 aut | |
| 700 | 1 | |a Bradley, Sophie J |e verfasserin |4 aut | |
| 700 | 1 | |a Le Gouill, Christian |e verfasserin |4 aut | |
| 700 | 1 | |a Bouvier, Michel |e verfasserin |4 aut | |
| 700 | 1 | |a Tobin, Andrew B |e verfasserin |4 aut | |
| 700 | 1 | |a Milligan, Graeme |e verfasserin |4 aut | |
| 773 | 0 | 8 | |i Enthalten in |t Nature chemical biology |d 2005 |g 15(2019), 5 vom: 16. Mai, Seite 489-498 |w (DE-627)NLM159707676 |x 1552-4469 |7 nnns |
| 773 | 1 | 8 | |g volume:15 |g year:2019 |g number:5 |g day:16 |g month:05 |g pages:489-498 |
| 856 | 4 | 0 | |u http://dx.doi.org/10.1038/s41589-019-0270-1 |3 Volltext |
| 912 | |a GBV_USEFLAG_A | ||
| 912 | |a GBV_NLM | ||
| 951 | |a AR | ||
| 952 | |d 15 |j 2019 |e 5 |b 16 |c 05 |h 489-498 | ||