SREBP-2 regulates gut peptide secretion through intestinal bitter taste receptor signaling in mice.
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ABSTRACT:
SUBMITTER: Jeon TI
PROVIDER: S-EPMC2564613 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:OBJECTIVES:Extracts of the hops plant have been shown to reduce weight and insulin resistance in rodents and humans, but elucidation of the mechanisms responsible for these benefits has been hindered by the use of heterogeneous hops-derived mixtures. Because hop extracts are used as flavoring agents for their bitter properties, we hypothesized that bitter taste receptors (Tas2rs) could be mediating their beneficial effects in metabolic disease. Studies have shown that exposure of cultured enteroendocrine cells to bitter tastants can stimulate release of hormones, including glucagon-like peptide 1 (GLP-1). These findings have led to the suggestion that activation of Tas2rs may be of benefit in diabetes, but this tenet has not been tested. Here, we have assessed the ability of a pure derivative of a hops isohumulone with anti-diabetic properties, KDT501, to signal through Tas2rs. We have further used this compound as a tool to systematically assess the impact of bitter taste receptor activation in obesity-diabetes. METHODS:KDT501 was tested in a panel of bitter taste receptor signaling assays. Diet-induced obese mice (DIO) were dosed orally with KDT501 and acute effects on glucose homeostasis determined. A wide range of metabolic parameters were evaluated in DIO mice chronically treated with KDT501 to establish the full impact of activating gut bitter taste signaling. RESULTS:We show that KDT501 signals through Tas2r108, one of 35 mouse Tas2rs. In DIO mice, acute treatment stimulated GLP-1 secretion and enhanced glucose tolerance. Chronic treatment caused weight and fat mass loss, increased energy expenditure, enhanced glucose tolerance and insulin sensitivity, normalized plasma lipids, and induced broad suppression of inflammatory markers. Chronic KDT501 treatment altered enteroendocrine hormone levels and bile acid homeostasis and stimulated sustained GLP-1 release. Combined treatment with a dipeptidyl peptidase IV inhibitor amplified the incretin-based benefits of this pure isohumulone. CONCLUSIONS:Activation of Tas2r108 in the gut results in a remodeling of enteroendocrine hormone release and bile acid metabolism that ameliorates multiple features of metabolic syndrome. Targeting extraoral bitter taste receptors may be useful in metabolic disease.
| S-EPMC6158035 | biostudies-literature
Project description:Caffeine, generally known as a stimulant of gastric acid secretion (GAS), is a bitter-tasting compound that activates several taste type 2 bitter receptors (TAS2Rs). TAS2Rs are expressed in the mouth and in several extraoral sites, e.g., in the gastrointestinal tract, in which their functional role still needs to be clarified. We hypothesized that caffeine evokes effects on GAS by activation of oral and gastric TAS2Rs and demonstrate that caffeine, when administered encapsulated, stimulates GAS, whereas oral administration of a caffeine solution delays GAS in healthy human subjects. Correlation analysis of data obtained from ingestion of the caffeine solution revealed an association between the magnitude of the GAS response and the perceived bitterness, suggesting a functional role of oral TAS2Rs in GAS. Expression of TAS2Rs, including cognate TAS2Rs for caffeine, was shown in human gastric epithelial cells of the corpus/fundus and in HGT-1 cells, a model for the study of GAS. In HGT-1 cells, various bitter compounds as well as caffeine stimulated proton secretion, whereby the caffeine-evoked effect was (i) shown to depend on one of its cognate receptor, TAS2R43, and adenylyl cyclase; and (ii) reduced by homoeriodictyol (HED), a known inhibitor of caffeine's bitter taste. This inhibitory effect of HED on caffeine-induced GAS was verified in healthy human subjects. These findings (i) demonstrate that bitter taste receptors in the stomach and the oral cavity are involved in the regulation of GAS and (ii) suggest that bitter tastants and bitter-masking compounds could be potentially useful therapeutics to regulate gastric pH.
| S-EPMC5544304 | biostudies-literature
Project description:AIMS/HYPOTHESIS:This study was designed to ascertain whether human enteroendocrine cells express bitter taste receptors, and whether activation of these receptors with bitter-tasting ligands induces secretion of glucagon-like peptide-1 (GLP-1) and peptide YY (PYY). METHODS:We used human enteroendocrine NCI-H716 cells, isolated duodenal segments from mice, and whole mice as our experimental systems for investigating stimuli and mechanisms underlying GLP-1- and PYY-stimulated release. We measured hormone levels by ELISA and determined bitter taste receptor expression by real-time quantitative PCR. We adopted a pharmacological approach using inhibitors and enhancers of downstream signalling pathways known to be involved in bitter taste transduction in taste bud cells to investigate these pathways in NCI-H716 cells. RESULTS:Using a pharmacological approach, we identified signalling pathways triggered by the denatonium benzoate (DB)-activated bitter receptors. This involved activation of ?-gustducin (G?gust)-the specific G-protein subunit that is also present in taste bud cells-reduction of intracellular cAMP levels and enhancement of phospholipase C (PLC) activity, which ultimately led to increased intracellular calcium concentrations and hormone release. Gavage of DB, followed by gavage of glucose, to db/db mice stimulated GLP-1 and subsequent insulin secretion, leading to lower blood glucose levels. CONCLUSIONS/INTERPRETATION:Our study demonstrates that activation of gut-expressed bitter taste receptors stimulates GLP-1 secretion in a PLC-dependent manner. In diabetic mice, DB (a ligand of bitter taste receptor cells), when given via gavage, lowers blood glucose levels in diabetic mice after oral glucose administration, through increased secretion of GLP-1.
| S-EPMC5160131 | biostudies-literature
Project description:Glucagon-like peptide-1 (GLP-1), released from gut endocrine L cells in response to glucose, regulates appetite, insulin secretion, and gut motility. How glucose given orally, but not systemically, induces GLP-1 secretion is unknown. We show that human duodenal L cells express sweet taste receptors, the taste G protein gustducin, and several other taste transduction elements. Mouse intestinal L cells also express alpha-gustducin. Ingestion of glucose by alpha-gustducin null mice revealed deficiencies in secretion of GLP-1 and the regulation of plasma insulin and glucose. Isolated small bowel and intestinal villi from alpha-gustducin null mice showed markedly defective GLP-1 secretion in response to glucose. The human L cell line NCI-H716 expresses alpha-gustducin, taste receptors, and several other taste signaling elements. GLP-1 release from NCI-H716 cells was promoted by sugars and the noncaloric sweetener sucralose, and blocked by the sweet receptor antagonist lactisole or siRNA for alpha-gustducin. We conclude that L cells of the gut "taste" glucose through the same mechanisms used by taste cells of the tongue. Modulating GLP-1 secretion in gut "taste cells" may provide an important treatment for obesity, diabetes and abnormal gut motility.
| S-EPMC1986614 | biostudies-literature
Project description:Neurotensin (NT), an intestinal peptide secreted from N cells in the small bowel, regulates a variety of physiological functions of the gastrointestinal tract, including secretion, gut motility, and intestinal growth. The class IA phosphatidylinositol 3-kinase (PI3K) family, which comprised of p110 catalytic (?, ? and ?) and p85 regulatory subunits, has been implicated in the regulation of hormone secretion from endocrine cells. However, the underlying mechanisms remain poorly understood. In particular, the role of PI3K in intestinal peptide secretion is not known. Here, we show that PI3K catalytic subunit, p110?, negatively regulates NT secretion in vitro and in vivo. We demonstrate that inhibition of p110?, but not p110?, induces NT release in BON, a human endocrine cell line, which expresses NT mRNA and produces NT peptide in a manner analogous to N cells, and QGP-1, a pancreatic endocrine cell line that produces NT peptide. In contrast, overexpression of p110? decreases NT secretion. Consistently, p110?-inhibition increases plasma NT levels in mice. To further delineate the mechanisms contributing to this effect, we demonstrate that inhibition of p110? increases NT granule trafficking by up-regulating ?-tubulin acetylation; NT secretion is prevented by overexpression of HDAC6, an ?-tubulin deacetylase. Moreover, ras-related protein Rab27A (a small G protein) and kinase D-interacting substrate of 220 kDa (Kidins220), which are associated with NT granules, play a negative and positive role, respectively, in p110?-inhibition-induced NT secretion. Our findings identify the critical role and novel mechanisms for the PI3K signaling pathway in the control of intestinal hormone granule transport and release.
| S-EPMC3404302 | biostudies-literature
Project description:Inflammatory bowel disease (IBD) is a debilitating immune-related condition that affects over 1.4?million Americans. Recent studies indicate that taste receptor signaling is involved in much more than sensing food flavor, and taste receptors have been localized in a variety of extra-oral tissues. One of the newly revealed functions of taste receptors and downstream signaling proteins is modulation of immune responses to microbes and parasites. We previously found that components of the taste receptor signaling pathway are expressed in subsets of the intestinal epithelial cells. ?-Gustducin, a key G-protein ? subunit involved in sweet, umami, and bitter taste receptor signaling, is expressed in the intestinal mucosa. In this study, we investigated the role of ?-gustducin in regulation of gut mucosal immunity and inflammation using ?-gustducin knockout mice in the dextran sulfate sodium (DSS)-induced IBD model. DSS is a chemical colitogen that can cause intestinal epithelial damage and inflammation. We analyzed DSS-induced colitis in ?-gustducin knockout versus wild-type control mice after administration of DSS in drinking water. Our results show that the knockout mice had aggravated weight loss, diarrhea, intestinal bleeding, and inflammation over the experimental period compared to wild-type mice, concurrent with augmented immune cell infiltration and increased expression of TNF and IFN-? but decreased expression of IL-13 and IL-5 in the colon. These results suggest that the taste receptor signaling pathway may play critical roles in regulating gut immune balance and inflammation.
| S-EPMC6003866 | biostudies-literature
Project description:T2Rs (bitter taste-sensing type 2 receptors) are expressed in the oral cavity to prevent ingestion of dietary toxins through taste avoidance. They are also expressed in other cell types, including gut enteroendocrine cells, where their physiological role is enigmatic. Previously, we proposed that T2R-dependent CCK (cholecystokinin) secretion from enteroendocrine cells limits absorption of dietary toxins, but an active mechanism was lacking. In the present study we show that T2R signalling activates ABCB1 (ATP-binding cassette B1) in intestinal cells through a CCK signalling mechanism. PTC (phenylthiocarbamide), an agonist for the T2R38 bitter receptor, increased ABCB1 expression in both intestinal cells and mouse intestine. PTC induction of ABCB1 was decreased by either T2R38 siRNA (small interfering RNA) or treatment with YM022, a gastrin receptor antagonist. Thus gut ABCB1 is regulated through signalling by CCK/gastrin released in response to PTC stimulation of T2R38 on enteroendocrine cells. We also show that PTC increases the efflux activity of ABCB1, suggesting that T2R signalling limits the absorption of bitter tasting/toxic substances through modulation of gut efflux membrane transporters.
| S-EPMC3319131 | biostudies-literature
Project description:(1) Background: Recent studies have investigated the expression of taste-related genes in the organs of various animals, including humans; however, data for additional taxa are needed to facilitate comparative analyses within and among species. (2) Methods: We investigated the expression of taste-related genes in the intestines of rhesus macaques, the non-human primates most commonly used in experimental models. (3) Results: Based on RNAseq and qRT-PCR, genes encoding bitter taste receptors and the G-protein gustducin were expressed in the gut of rhesus macaques. RNAscope analysis showed that one of the bitter receptors, TAS2R38, was expressed in some cells in the small intestine, and immunohistochemical analysis revealed the presence of T2R38-positive cells in the villi of the intestines. (4) Conclusions: These results suggest that bitter receptors are expressed in the gut of rhesus macaques, supporting the use of macaques as a model for studies of human taste, including gut analyses.
| S-EPMC7037741 | biostudies-literature
Project description:Taste receptors exist in several organs from tongue to colon and have diverse functions dependent on specific cell type. In enteroendocrine L-cells, stimulation of taste receptor signaling induces incretin hormones. Among incretin hormones, glucagon-like peptide-1 (GLP-1) induces insulinotropic action by activating GLP-1 receptor of pancreatic ?-cells. However, GLP-1 mimetic medicines have reported clinical side effects, such as autoimmune hepatitis, acute kidney injury, pancreatitis, and pancreatic cancer. Here, we hypothesized that if natural components in ethnomedicines can activate agonistic action of taste receptor; they may stimulate GLP-1 and therefore, could be developed as safe and applicable medicines to type 2 diabetes mellitus (T2DM) with minimal side effects. Cucurbitacin B (CuB) is composed of triterpenoid structure and its structural character, that represents bitterness, can stimulate AMP-activated protein kinase (AMPK) pathway. CuB ameliorated hyperglycemia by activating intestinal AMPK levels and by inducing plasma GLP-1 and insulin release in diabetic mice. This hypoglycemic action was decreased in dorsomorphin-injected mice and ?-gustducin null mice. Moreover, systemic inhibition study in differentiated NCI-H716 cell line showed that CuB-mediated GLP-1 secretion was involved in activation of AMPK through ?-gustducin and G??-signaling of taste receptors. In summary, we conclude that, CuB represents novel hypoglycemic agents by activation of AMPK and stimulation of GLP-1 in differentiated enteroendocrine L-cells. These results suggest that taste receptor signaling-based therapeutic agents within tremendously diverse ethnomedicines, could be applied to developing therapeutics for T2DM patients.
| S-EPMC6161541 | biostudies-literature
Project description:Intestinal chemosensory signaling pathways involving the gustatory G-protein, gustducin, and bitter taste receptors (TAS2R) have been implicated in gut hormone release. Alterations in gut hormone profiles may contribute to the success of bariatric surgery. This study investigated the involvement of the gustatory signaling pathway in the development of diet-induced obesity and the therapeutic potential of targeting TAS2Rs to induce body weight loss. α-gustducin-deficient (α-gust-/-) mice became less obese than wild type (WT) mice when fed a high-fat diet (HFD). White adipose tissue (WAT) mass was lower in α-gust-/- mice due to increased heat production as a result of increases in brown adipose tissue (BAT) thermogenic activity, involving increased protein expression of uncoupling protein 1. Intra-gastric treatment of obese WT and α-gust-/- mice with the bitter agonists denatonium benzoate (DB) or quinine (Q) during 4 weeks resulted in an α-gustducin-dependent decrease in body weight gain associated with a decrease in food intake (DB), but not involving major changes in gut peptide release. Both WAT and 3T3-F442A pre-adipocytes express TAS2Rs. Treatment of pre-adipocytes with DB or Q decreased differentiation into mature adipocytes. In conclusion, interfering with the gustatory signaling pathway protects against the development of HFD-induced obesity presumably through promoting BAT activity. Intra-gastric bitter treatment inhibits weight gain, possibly by directly affecting adipocyte metabolism.
| S-EPMC4686985 | biostudies-literature