Aroma compound diacetyl suppresses glucagon-like peptide-1 production and secretion in STC-1 cells
Introduction
The gut hormone glucagon-like peptide 1 (GLP-1) has attracted considerable interest in recent years due to its ability to enhance glucose-dependent insulin secretion, promote pancreatic β-cell proliferation and reduce food intake. It has also been reported that GLP-1 may reduce the rewarding and reinforcing properties of palatable foods (Dickson et al., 2012). Secretion of this nutrient-responsive hormone is impaired in obesity and type 2 diabetes (Toft-Nielsen et al., 2001) and infusion of GLP-1 has been shown to improve glycemia and reduce food intake in obese patients (Nauck et al., 1998).
GLP-1 is produced by L cells of the distal jejunum and ileum following tissue-specific proteolytic processing of the proglucagon gene (Baggio & Drucker, 2007). The arrival of carbohydrate, fat and protein in the gut lumen triggers GLP-1 release (Bruen, O'Halloran, Cashman, & Giblin, 2012). Inhibition of GLP-1 by food has not been extensively studied. Within the L cells, GLP-1 secretion occurs in response to an increase in intracellular levels of cyclic adenosine monophosphate (cAMP) and Ca2+ (Tolhurst, Reimann, & Gribble, 2009). Changes in these mediators are brought about by nutrient uptake pathways, metabolic closures of potassium channels and/or activation of nutrient-responsive G protein-coupled receptors (GPCRs) (Reimann et al., 2012). These GPCRs play various roles in GLP-1 secretion. The taste GPCRs, T1r3/T1r2, and the G protein α-gustducin are involved in the secretion of GLP-1 in response to sugars (Jang et al., 2007). On the other hand, free fatty acids (FFA) can induce GLP-1 secretion via the GPCRs, GPR40 and GPR120 (Hirasawa et al., 2005, Reimann et al., 2012). GPR120 is highly expressed in enteroendocrine L cells (Anbazhagan et al., 2016, Hirasawa et al., 2005) and is activated in response to unsaturated long-chain FFA (Tanaka et al., 2008). Recent evidence also suggests that GPR120 plays an important role in the orosensory detection and preference for fats (Cartoni et al., 2010). GPR120 is classified as a Gq/11-coupled receptor, capable of increasing GLP-1 secretion via phospholipase Cβ and intracellular Ca2 signalling (Blad, Tang, & Offermanns, 2012) although there is also some evidence of signalling promiscuity (Reimann et al., 2012, Tsukahara et al., 2015).
Whilst the role of taste receptors and tastants in GLP-1 secretion has been widely investigated in recent years, there is less information available on whether aromatic compounds may also influence satiety signals. The aroma of a food plays an important role in food palatability and intake (Massolt et al., 2010, Ruijschop et al., 2009). Whilst such effects may be mediated through neural pathways, it is also possible that aroma compounds may influence satiety signals. Indeed, it has been demonstrated that food-derived odorants present in the gut lumen may stimulate serotonin release via olfactory receptors present in human enterochromaffin cells (Braun, Voland, Kunz, Prinz, & Gratzl, 2007) and aroma intensity certainly influences perceived satiation (Ruijschop et al., 2009).
Diacetyl (2,3-butanedione) is a volatile favour compound that occurs naturally in several foods, such as butter, milk, cheese, fruit and coffee and has a characteristic buttery aroma (Bartowsky & Henschke, 2004). It is primarily produced by citrate fermenting lactic acid bacteria during pyruvate metabolism. It is widely used in the flavouring industry. This pleasant buttery aroma is perceived as a positive attribute by consumers and has been shown to play a significant role in food preference and palatability (Liggett, Drake, & Delwiche, 2008).
The present study was undertaken to evaluate whether diacetyl alters GLP-1 production and secretion, using the murine secretin tumor cell line, STC-1. STC-1 is a popular and reliable enteroendocrine model to investigate gut hormone production and secretion. Similar to native L cells, STC-1 cells secrete GLP-1 in response to sugars, peptides, fatty acids, sweeteners, bitter tastants, food bioactives, hormones and bile (McCarthy et al., 2015). However levels of response may differ to the native state (Kuhre et al., 2016). STC-1 cells also express GPR120, taste receptors (T1r1, T1r2, T1r3) and α-gustducin (Hirasawa et al., 2005, Wu et al., 2002) and are recognized as a good model for taste signalling (Saitoh, Hirano, & Nishimura, 2007).
Section snippets
Chemicals
Diacetyl, KREBS ringers bicarbonate buffer, nicardipine, nitrendipine, tolbutamide, pertussis toxin, polyethylene glycol, DMSO, Hanks Balanced Salt Solution, DMEM media, glucose, L-glutamine, foetal bovine serum, penicillin, streptomycin, 3-Isobutyl-1-methylxanthine (IBMX), forskolin, poly-l-lysine coated glass-slides, paraformaldehyde, HEPES, NaCl, EDTA, ethylene glycol tetraacetic acid, Nonident P40, dithiothreitol, Na3VO4, phenylmethysulphonyl fluoride, aprotinin, leupeptin, NaF, NaPPi,
Diacetyl reduces proglucagon mRNA levels and total GLP-1 secretion in the presence of 10mM glucose
STC-1 cells were exposed to physiologically relevant concentrations of the volatile flavour compound, diacetyl. As in other studies (Zhou & Pestka, 2015), exposures were performed in the presence of the known stimulator, glucose. In our study, experiments were performed in KREBS Ringers bicarbonate buffer, which contains 10 mM glucose. Exposure of STC-1 cells to diacetyl resulted in a significant (P < 0.05) dose-dependent decrease in proglucagon mRNA levels compared to the vehicle control at all
Discussion
The widely used flavour ingredient diacetyl inhibits production and secretion of GLP-1 by intestinal endocrine cells in vitro. This damping effect on GLP-1 appears to be mediated by recruiting GPR120 to the cell surface, increasing intercellular cAMP levels and increasing GPR120 synthesis. The mechanism of GLP-1 reduction by diacetyl appears to be electroneutral, as evidenced by independence from K+ATP channels and voltage-gated Ca2+ channels. The α-gustducin taste pathway also does not appear
Acknowledgements
T. McCarthy was in receipt of a Teagasc Walsh Fellowship. This work was funded by Enterprise Ireland under Grant Number CC20080001. We would like to thank John Hannon for technical assistance using the volatile compound, diacetyl.
References (40)
- et al.
Biology of incretins: GLP-1 and GIP
Gastroenterology
(2007) - et al.
The 'buttery' attribute of wine–diacetyl–desirability, spoilage and beyond
International Journal of Food Microbiology
(2004) - et al.
Enterochromaffin cells of the human gut: sensors for spices and odorants
Gastroenterology
(2007) - et al.
Lactisole interacts with the transmembrane domains of human T1R3 to inhibit sweet taste
Journal of Biological Chemistry
(2005) - et al.
Free fatty acids inhibit serum deprivation-induced apoptosis through GPR120 in a murine enteroendocrine cell line STC-1
Journal of Biological Chemistry
(2005) Reward mechanisms in obesity: new insights and future directions
Neuron
(2011)- et al.
Impact of flavor attributes on consumer liking of Swiss cheese
Journal of Dairy Science
(2008) - et al.
Appetite suppression through smelling of dark chocolate correlates with changes in ghrelin in young women
Regulatory Peptides
(2010) Molecular mechanisms underlying nutrient detection by incretin-secreting cells
International Dairy Journal
(2010)- et al.
G-protein-coupled receptors in intestinal chemosensation
Cell Metabolism
(2012)
Olfactory receptor and neural pathway responsible for highly selective sensing of musk odors
Neuron
Tumor necrosis factor alpha decreases glucagon-like peptide-2 expression by up-regulating G-protein-coupled receptor 120 in Crohn disease
American Journal of Pathology
A novel anti-inflammatory role of GPR120 in intestinal epithelial cells
American Journal of Physiology. Cell Physiology
G protein-coupled receptors for energy metabolites as new therapeutic targets
Nature Reviews Drug Discovery
The effects of food components on hormonal signalling in gastrointestinal enteroendocrine cells
Food Function
Taste preference for fatty acids is mediated by GPR40 and GPR120
Journal of Neuroscience
Bitter stimuli induce Ca2+ signaling and CCK release in enteroendocrine STC-1 cells: role of L-type voltage-sensitive Ca2+ channels
American Journal of Physiology. Cell Physiology
The glucagon-like peptide 1 (GLP-1) analogue, exendin-4, decreases the rewarding value of food: a new role for mesolimbic GLP-1 receptors
Journal of Neuroscience
Protein hydrolysates stimulate proglucagon gene transcription in intestinal endocrine cells via two elements related to cyclic AMP response element
Diabetologia
Grape-seed procyanidins modulate cellular membrane potential and nutrient-induced GLP-1 secretion in STC-1 cells
American Journal of Physiology. Cell Physiology
Cited by (5)
Plant-based fermented foods and the satiety cascade: A systematic review of randomized controlled trials
2023, Trends in Food Science and TechnologyIrish Cheddar cheese increases glucagon-like peptide-1 secretion in vitro but bioactivity is lost during gut transit
2018, Food ChemistryCitation Excerpt :Despite differences in bioactivity, butyric acid was present in equivalent amounts in the potent C2-WSE-8M and the least potent C6-WSE-8M. In a previous study, diacetyl was found to dose-dependently suppress secretion of GLP-1 from the STC-1 cell line (McCarthy, et al., 2017). Surprisingly C2-WSE-8M stimulated the highest GLP-1 level and yet contained more diacetyl than C6-WSE-8M.
Voltammetric determination of trace amounts of diacetyl at a mercury meniscus modified silver solid amalgam electrode following gas-diffusion microextraction
2017, TalantaCitation Excerpt :Diacetyl is the most important of those compounds in food technology, mainly due to a characteristic butter like aroma that can affect the organoleptic quality of products [1–3]. In recent studies, researchers have concluded that diacetyl has the ability to reduce satiety signals, which may contribute to the overconsumption of some foods [4]. Moreover, it has been linked with relevant health concerns, with continuous diacetyl exposure susceptible of causing pulmonary disease, Alzheimer disease and cancer [5–7].