Gustducin couples fatty acid receptors to GLP-1 release in colon

Abstract

taste receptor subunits and ␣-gustducin found in enteroendocrine cells of the small intestine have been implicated in release of the incretin hormones glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) in response to glucose and noncaloric sweeteners. ␣-Gustducin has also been found in colon, although its function there is unclear. We examined expression of ␣-gustducin, GLP-1, and GIP throughout the intestine. The number of ␣-gustducin-expressing cells and those coexpressing ␣-gustducin together with GLP-1 and/or GIP increased from small intestine to colon. ␣-Gustducin also was coexpressed with fatty acid G protein-coupled receptor (GPR) 40, GPR41, GPR43, GPR119, GPR120, and bile acid G protein-coupled receptor TGR5 in enteroendocrine cells of the colon. In colon, GPR43 was coexpressed with GPR119 and GPR120, but not with TGR5. Treatment of colonic mucosa isolated from wild-type mice with acetate, butyrate, oleic acid, oleoylethanolamide, or lithocholic acid stimulated GLP-1 secretion. However, GLP-1 release in response to these fatty acids was impaired in colonic tissue from ␣-gustducin knockout mice.␣-gustducin; glucose-dependent insulinotropic polypeptide; glucagon-like peptide 1; fatty acid receptors; enteroendocrine cell THE INCRETIN HORMONES glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are estimated to account for ϳ50 -70% of total insulin release after oral glucose administration (13,30,59). The meal-related GLP-1 response in type 2 diabetes is decreased, which may contribute to the decreased incretin effect in this population (58,86).The sweet taste receptor subunits T1r2 and T1r3, and the G protein ␣-subunit ␣-gustducin, initially found in taste cells (48,54,55,60,91), have also been shown to be present in enteroendocrine and brush cells of the small intestine (3, 14, 29, 51). ␣-Gustducin and T1r receptors are also present in the small intestine's L-and K-type enteroendocrine cells, which release GLP-1 and GIP, respectively, in response to glucose in the gut lumen (35). In response to glucose gavage, ␣-gustducin null mice do not show the elevation of serum levels of GLP-1 found in gavaged wild-type mice (35). Furthermore, sweetenerstimulated GLP-1 release from L cell lines can be inhibited by small-interfering RNA against ␣-gustducin or pharmacological blocking of the T1r2ϩT1r3 sweet receptor (35, 51). In addition, other mechanisms independent of ␣-gustducin and T1rs, including sodium glucose cotransporter-1 (SGLT1) and ATPsensitive K ϩ channels (K ATP ), are known to regulate GLP-1 release from primary L cells (69).␣-Gustducin is also expressed with peptide YY (PYY) and GLP-1 in L cells of the human colon (74), although its functions in these cells are unknown. The lumen of the colon lacks dietary sugars, but is filled with microbiota, nondigestible matter, and fermentation products, such as short-chain fatty acids (SCFAs), ammonia, phenols, amines, and bile acids (12,23,50,84). Medium-and long-chain fatty acids (LCFAs) are a...

Inhibitory Effect of Oleic Acid on Octanoylated Ghrelin Production

“…The decrease in octanoylated ghrelin secretion after feeding is partially induced by long-chain fatty acids that act directly on gastric GPR120-expressing ghrelin cells 32 . In addition, it was reported that the G protein α-gustducin is also involved in ghrelin octanoylation 31 and that α-gustducin could couple GPR120 33 . In our study, stearic acid, oleic acid, linoleic acid, and α-linolenic acid could have suppressed the release of octanoylated ghrelin via GPR120 and/or α-gustducin-mediated mechanism.…”

Short-Chain Fatty Acid Receptor and Its Contribution to Glucagon-Like Peptide-1 Release

“…On the other hand, individual FFA2- or FFA3-deficient mice showed low GLP-1 release in response to SCFAs, indicating that FFA3 is also involved in SCFA-evoked GLP-1 release [14,27]. High-dose (80 m M ) acetate-evoked GLP-1 releases were also observed in the isolated colonic mucosa from wild-type mice, but not from α-gustducin knockout mice [28]. As gustducin is a G i family member, the possibility was raised that G i -coupled FFA2 and/or FFA3 elicit GLP-1 releases in the colon.…”

Taste Receptor Gene Expression Outside the Gustatory System

“…Recently, both G protein α-subunits were found to be expressed in ghrelin-producing cells of the oxyntic glands of the stomach [12]. Numerous reports confirmed and extended the initial findings of taste-signaling elements in the GI tract to most regions of the Taste Receptor Gene Expression Outside the Gustatory System alimentary canal [2,4,16,17,23,108,117,122], with the colon harboring the highest number of α-gustducin-positive cells [123]. Noteworthy is the finding of a numerically important α-gustducin-expressing cell population confined to a relative restricted region of the stomach, the limiting ridge [112].…”

“…Regarding the co-expression of taste transduction elements with taste receptors, it turned out that TRPM5-positive cells in mouse small intestine do neither express Tas1rs nor Tas2rs [2], while in the same regions α-gustducin exhibits a certain degree of colocalization with the Tas1r subunits [4,11,17]. Moreover, in the GI tract taste-related signaling elements may facilitate signal propagation of G protein-coupled receptors currently not considered as bona fide taste receptors such as fatty acid receptors and oleoylethanolamide and bile acid receptors which are co-expressed with α-gustducin in mouse colon [123].…”

“…In mouse jejunum and in human ileum, enterochromaffin (EC) cells producing serotonin were found to express α-gustducin [23], TAS1R3, and TAS2R1 [107]. In the colon, α-gustducin is expressed again in L and K cells but not in EC cells [20,123]. Also in the stomach of mouse, the Tas1r3 subunit was found in gastrin-positive G cells [111].…”