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Wang C, Zhou J, Liu X, Zhu F, Li J, Xu W, Liu J. Quercetin Enhances GLP-1 Secretion via TAS2R38-Mediated PLC Signaling in Enteroendocrine L-Cells. Mol Nutr Food Res 2025:e70109. [PMID: 40364471 DOI: 10.1002/mnfr.70109] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2025] [Revised: 04/13/2025] [Accepted: 04/28/2025] [Indexed: 05/15/2025]
Abstract
Quercetin (QC), a natural flavonoid, has shown potential in regulating glucose homeostasis by promoting glucagon-like peptide-1 (GLP-1) secretion. This study investigates the role of the bitter taste receptor TAS2R38 and the phospholipase C (PLC) signaling pathway in QC-induced GLP-1 secretion from enteroendocrine NCI-H716 cells. Molecular docking revealed strong binding between QC and TAS2R38. QC significantly enhanced GLP-1 secretion, which was attenuated by TAS2R38 siRNA and PLC inhibitors. These findings suggest that QC stimulates GLP-1 release through TAS2R38-mediated PLC signaling, offering a novel mechanism for QC's antidiabetic effects.
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Affiliation(s)
- Chenxuan Wang
- College of Food Science and Technology, Hebei Normal University of Science and Technology, Qinhuangdao, China
| | - Jiefang Zhou
- College of Food Science and Technology, Hebei Normal University of Science and Technology, Qinhuangdao, China
| | - Xiaojing Liu
- College of Food Science and Technology, Hebei Normal University of Science and Technology, Qinhuangdao, China
| | - Fengmei Zhu
- College of Food Science and Technology, Hebei Normal University of Science and Technology, Qinhuangdao, China
| | - Jun Li
- College of Food Science and Technology, Hebei Normal University of Science and Technology, Qinhuangdao, China
| | - Wentao Xu
- Department of Nutrition and Health, China Agricultural University, Beijing, China
| | - Jinjin Liu
- College of Animal Science, Hebei Normal University of Science and Technology, Qinhuangdao, China
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2
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Maevskaya MV, Okovityi SV. Lactitol properties in the treatment of patients with lifestyle-related diseases. MEDITSINSKIY SOVET = MEDICAL COUNCIL 2024:162-169. [DOI: 10.21518/ms2024-184] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
Abstract
Russia and most countries of the world are currently facing pressures on their health services because of the growing number of diseases associated with unhealthy lifestyles: type 2 diabetes, obesity, non-alcoholic fatty liver disease, etc. Lifestyle modification is the first prerequisite in the treatment of non-alcoholic fatty liver disease and other diseases associated with unhealthy lifestyle. The use of lactitol provides the opportunity to make this process more effective, as it is able to increase the production of butyrate, reduce the damage to the intestine barrier structure, and interact with sweet-taste receptors. Lactitol has a low glycaemic index, it is not absorbed in the intestine and is fermented like dietary fibres. The results of the studies showed that the metabolic response to this drug corresponds to a lower increase in plasma glucose, insulin and C-peptide levels compared to the use of glucose in healthy, non-obese men. It has been shown through various experiments in animals and in humans that lactitol also reduces the plasma triglyceride levels, probably due to reduced triglyceride absorption as a result of accelerated transit of intestinal contents. An important property of the drug is its ability to increase the glucagon-like peptide-1 (GLP-1) and PYY levels, which is accompanied by delayed gastric emptying and reduced hunger, which is essential in the treatment of obesity, type 2 diabetes mellitus and non-alcoholic fatty liver disease. A 120-day randomized controlled trial was conducted to assess the efficacy, safety, and tolerability of lactitol in 139 patients with nonalcoholic fatty liver disease. Twice-daily administration of lactitol 6 g in addition to lifestyle modification events has been shown to increase their efficacy expressed as a significant decrease in ALT levels and an increase in the AST/ALT ratio compared to control subjects. Lactitol can be considered as a metabolic corrector and used in the treatment of diseases associated with an unhealthy lifestyle.
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Affiliation(s)
- M. V. Maevskaya
- Sechenov First Moscow State Medical University (Sechenov University)
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3
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Zhang Y, Chen L, Gao J, Cheng Y, Luo F, Bai X, Ding H. Nutritive/non-nutritive sweeteners and high fat diet contribute to dysregulation of sweet taste receptors and metabolic derangements in oral, intestinal and central nervous tissues. Eur J Nutr 2023; 62:3149-3159. [PMID: 37537344 DOI: 10.1007/s00394-023-03187-9] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2022] [Accepted: 05/31/2023] [Indexed: 08/05/2023]
Abstract
OBJECTIVES Overconsumption of non-nutritive sweeteners is associated with obesity, whereas the underlying mechanisms remain controversial. This study aimed to investigate the effects of long-term consumption of nutritive or non-nutritive sweeteners with or without high fat diet on sweet taste receptor expression in nutrient-sensing tissues and energy regulation dependent on sweet-sensing. METHODS 50 Male Sprague-Dawley rats (140-160 g) were assigned to 10 groups (n = 5/group). All received fructose at 2.5% or 10%, sucralose at 0.01% or 0.015% or water with a normal chow diet or high fat diet for 12 weeks. Food and drink intake were monitored daily. Oral glucose tolerance test and intraperitoneal glucose tolerance test were performed at week 10 and 11 respectively. Serum was obtained for measurement of biochemical parameters. Tongue, duodenum, jejunum, ileum, colon and hypothalamus were rapidly removed to assess gene expression. RESULTS Long-term consumption of sweeteners impaired glucose tolerance, increased calorie intake and body weight. A significant upregulation of sweet taste receptor expression was observed in all the four intestinal segments in groups fed 0.01% sucralose or 0.015% sucralose, most strikingly in the ileum, accompanied by elevated serum glucagon-like peptide-1 levels and up-regulated expression of sodium-dependent glucose cotransporter 1 and glucose transporter 2. A significant down-regulation in the tongue and hypothalamus was observed in groups fed 10% fructose or 0.015% sucralose, with alterations in hypothalamic appetite signals. The presence of high fat diet differentially modulates sweet taste perception in nutrient-sensing tissues. CONCLUSIONS Long-term consumption of whether nutritive sweeteners or non-nutritive sweeteners combined with high fat diet contribute to dysregulation of sweet taste receptor expression in oral, intestinal and central nervous tissues.
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Affiliation(s)
- Yiyuan Zhang
- Key Laboratory of Combinatorial Biosynthesis and Drug Discovery, Wuhan University, Wuhan, 430000, China
| | - Lu Chen
- Key Laboratory of Combinatorial Biosynthesis and Drug Discovery, Wuhan University, Wuhan, 430000, China
| | - Jiefang Gao
- Key Laboratory of Combinatorial Biosynthesis and Drug Discovery, Wuhan University, Wuhan, 430000, China
| | - Yahong Cheng
- Key Laboratory of Combinatorial Biosynthesis and Drug Discovery, Wuhan University, Wuhan, 430000, China
| | - Fei Luo
- Key Laboratory of Combinatorial Biosynthesis and Drug Discovery, Wuhan University, Wuhan, 430000, China
| | - Xinying Bai
- Key Laboratory of Combinatorial Biosynthesis and Drug Discovery, Wuhan University, Wuhan, 430000, China
| | - Hong Ding
- Key Laboratory of Combinatorial Biosynthesis and Drug Discovery, Wuhan University, Wuhan, 430000, China.
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4
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Chuong V, Farokhnia M, Khom S, Pince CL, Elvig SK, Vlkolinsky R, Marchette RC, Koob GF, Roberto M, Vendruscolo LF, Leggio L. The glucagon-like peptide-1 (GLP-1) analogue semaglutide reduces alcohol drinking and modulates central GABA neurotransmission. JCI Insight 2023; 8:e170671. [PMID: 37192005 PMCID: PMC10371247 DOI: 10.1172/jci.insight.170671] [Citation(s) in RCA: 67] [Impact Index Per Article: 33.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2023] [Accepted: 05/10/2023] [Indexed: 05/17/2023] Open
Abstract
Growing evidence indicates that the glucagon-like peptide-1 (GLP-1) system is involved in the neurobiology of addictive behaviors, and GLP-1 analogues may be used for the treatment of alcohol use disorder (AUD). Here, we examined the effects of semaglutide, a long-acting GLP-1 analogue, on biobehavioral correlates of alcohol use in rodents. A drinking-in-the-dark procedure was used to test the effects of semaglutide on binge-like drinking in male and female mice. We also tested the effects of semaglutide on binge-like and dependence-induced alcohol drinking in male and female rats, as well as acute effects of semaglutide on spontaneous inhibitory postsynaptic currents (sIPSCs) from central amygdala (CeA) and infralimbic cortex (ILC) neurons. Semaglutide dose-dependently reduced binge-like alcohol drinking in mice; a similar effect was observed on the intake of other caloric/noncaloric solutions. Semaglutide also reduced binge-like and dependence-induced alcohol drinking in rats. Semaglutide increased sIPSC frequency in CeA and ILC neurons from alcohol-naive rats, suggesting enhanced GABA release, but had no overall effect on GABA transmission in alcohol-dependent rats. In conclusion, the GLP-1 analogue semaglutide decreased alcohol intake across different drinking models and species and modulated central GABA neurotransmission, providing support for clinical testing of semaglutide as a potentially novel pharmacotherapy for AUD.
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Affiliation(s)
- Vicky Chuong
- Clinical Psychoneuroendocrinology and Neuropsychopharmacology Section, Translational Addiction Medicine Branch, National Institute on Drug Abuse Intramural Research Program (NIDA IRP) and National Institute on Alcohol Abuse and Alcoholism Division of Intramural Clinical and Biological Research (NIAAA DICBR), NIH, Baltimore and Bethesda, Maryland, USA
- Neurobiology of Addiction Section, NIDA IRP, NIH, Baltimore, Maryland, USA
| | - Mehdi Farokhnia
- Clinical Psychoneuroendocrinology and Neuropsychopharmacology Section, Translational Addiction Medicine Branch, National Institute on Drug Abuse Intramural Research Program (NIDA IRP) and National Institute on Alcohol Abuse and Alcoholism Division of Intramural Clinical and Biological Research (NIAAA DICBR), NIH, Baltimore and Bethesda, Maryland, USA
| | - Sophia Khom
- Department of Molecular Medicine, The Scripps Research Institute, La Jolla, California, USA
- Department of Pharmaceutical Sciences, University of Vienna, Vienna, Austria
| | - Claire L. Pince
- Clinical Psychoneuroendocrinology and Neuropsychopharmacology Section, Translational Addiction Medicine Branch, National Institute on Drug Abuse Intramural Research Program (NIDA IRP) and National Institute on Alcohol Abuse and Alcoholism Division of Intramural Clinical and Biological Research (NIAAA DICBR), NIH, Baltimore and Bethesda, Maryland, USA
- Neurobiology of Addiction Section, NIDA IRP, NIH, Baltimore, Maryland, USA
| | - Sophie K. Elvig
- Neurobiology of Addiction Section, NIDA IRP, NIH, Baltimore, Maryland, USA
| | - Roman Vlkolinsky
- Department of Molecular Medicine, The Scripps Research Institute, La Jolla, California, USA
| | | | - George F. Koob
- Neurobiology of Addiction Section, NIDA IRP, NIH, Baltimore, Maryland, USA
| | - Marisa Roberto
- Department of Molecular Medicine, The Scripps Research Institute, La Jolla, California, USA
| | - Leandro F. Vendruscolo
- Stress and Addiction Neuroscience Unit, NIDA IRP and National Institute on Alcohol Abuse and Alcoholism Division of Intramural Clinical and Biological Research, National Institutes of Health, Baltimore, Maryland, USA
| | - Lorenzo Leggio
- Clinical Psychoneuroendocrinology and Neuropsychopharmacology Section, Translational Addiction Medicine Branch, National Institute on Drug Abuse Intramural Research Program (NIDA IRP) and National Institute on Alcohol Abuse and Alcoholism Division of Intramural Clinical and Biological Research (NIAAA DICBR), NIH, Baltimore and Bethesda, Maryland, USA
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5
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Wang Y, Geng R, Zhao Y, Fang J, Li M, Kang SG, Huang K, Tong T. The gut odorant receptor and taste receptor make sense of dietary components: A focus on gut hormone secretion. Crit Rev Food Sci Nutr 2023; 64:6975-6989. [PMID: 36785901 DOI: 10.1080/10408398.2023.2177610] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/15/2023]
Abstract
Odorant receptors (ORs) and taste receptors (TRs) are expressed primarily in the nose and tongue in which they transduce electrical signals to the brain. Advances in deciphering the dietary component-sensing mechanisms in the nose and tongue prompted research on the role of gut chemosensory cells. Acting as the pivotal interface between the body and dietary cues, gut cells "smell" and "taste" dietary components and metabolites by taking advantage of chemoreceptors-ORs and TRs, to maintain physiological homeostasis. Here, we reviewed this novel field, highlighting the latest discoveries pertinent to gut ORs and TRs responding to dietary components, their impacts on gut hormone secretion, and the mechanisms involved. Recent studies indicate that gut cells sense dietary components including fatty acid, carbohydrate, and phytochemical by activating relevant ORs, thereby modulating GLP-1, PYY, CCK, and 5-HT secretion. Similarly, gut sweet, umami, and bitter receptors can regulate the gut hormone secretion and maintain homeostasis in response to dietary components. A deeper understanding of the favorable influence of dietary components on gut hormone secretion via gut ORs and TRs, coupled with the facts that gut hormones are involved in diverse physiological or pathophysiological phenomena, may ultimately lead to a promising treatment for various human diseases.
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Affiliation(s)
- Yanan Wang
- Key Laboratory of Precision Nutrition and Food Quality, Key Laboratory of Functional Dairy, Ministry of Education; College of Food Science and Nutritional Engineering, China Agricultural University, Beijing, PR China
| | - Ruixuan Geng
- Key Laboratory of Precision Nutrition and Food Quality, Key Laboratory of Functional Dairy, Ministry of Education; College of Food Science and Nutritional Engineering, China Agricultural University, Beijing, PR China
| | - Yuhan Zhao
- Key Laboratory of Precision Nutrition and Food Quality, Key Laboratory of Functional Dairy, Ministry of Education; College of Food Science and Nutritional Engineering, China Agricultural University, Beijing, PR China
| | - Jingjing Fang
- Key Laboratory of Precision Nutrition and Food Quality, Key Laboratory of Functional Dairy, Ministry of Education; College of Food Science and Nutritional Engineering, China Agricultural University, Beijing, PR China
| | - Mengjie Li
- Key Laboratory of Precision Nutrition and Food Quality, Key Laboratory of Functional Dairy, Ministry of Education; College of Food Science and Nutritional Engineering, China Agricultural University, Beijing, PR China
| | - Seong-Gook Kang
- Department of Food Engineering, Mokpo National University, Muangun, Korea
| | - Kunlun Huang
- Key Laboratory of Precision Nutrition and Food Quality, Key Laboratory of Functional Dairy, Ministry of Education; College of Food Science and Nutritional Engineering, China Agricultural University, Beijing, PR China
- Key Laboratory of Safety Assessment of Genetically Modified Organism (Food Safety), Ministry of Agriculture, Beijing, PR China
- Beijing Laboratory for Food Quality and Safety, Beijing, PR China
| | - Tao Tong
- Key Laboratory of Precision Nutrition and Food Quality, Key Laboratory of Functional Dairy, Ministry of Education; College of Food Science and Nutritional Engineering, China Agricultural University, Beijing, PR China
- Key Laboratory of Safety Assessment of Genetically Modified Organism (Food Safety), Ministry of Agriculture, Beijing, PR China
- Beijing Laboratory for Food Quality and Safety, Beijing, PR China
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6
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Ben Abu N, Ben Shoshan-Galeczki Y, Malach E, Y Niv M. The T1R3 subunit of the sweet taste receptor is activated by D2O in transmembrane domain-dependent manner. Chem Senses 2023; 48:bjad032. [PMID: 37589415 DOI: 10.1093/chemse/bjad032] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2023] [Indexed: 08/18/2023] Open
Abstract
Deuterium oxide (D2O) is water in which the heavier and rare isotope deuterium replaces both hydrogens. We have previously shown that D2O has a distinctly sweet taste, mediated by the T1R2/T1R3 sweet taste receptor. Here, we explore the effect of heavy water on T1R2 and T1R3 subunits. We show that D2O activates T1R3-transfected HEK293T cells similarly to T1R2/T1R3-transfected cells. The response to glucose dissolved in D2O is higher than in water. Mutations of phenylalanine at position 7305.40 in the transmembrane domain of T1R3 to alanine, leucine, or tyrosine impair or diminish activation by D2O, suggesting a critical role for T1R3 TMD domain in relaying the heavy water signal.
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Affiliation(s)
- Natalie Ben Abu
- The Institute of Biochemistry, Food Science and Nutrition, Robert H. Smith Faculty of Agriculture, Food and Environment, The Hebrew University of Jerusalem, P.O. Box 12, Rehovot 76100, Israel
| | - Yaron Ben Shoshan-Galeczki
- The Institute of Biochemistry, Food Science and Nutrition, Robert H. Smith Faculty of Agriculture, Food and Environment, The Hebrew University of Jerusalem, P.O. Box 12, Rehovot 76100, Israel
| | - Einav Malach
- The Institute of Biochemistry, Food Science and Nutrition, Robert H. Smith Faculty of Agriculture, Food and Environment, The Hebrew University of Jerusalem, P.O. Box 12, Rehovot 76100, Israel
| | - Masha Y Niv
- The Institute of Biochemistry, Food Science and Nutrition, Robert H. Smith Faculty of Agriculture, Food and Environment, The Hebrew University of Jerusalem, P.O. Box 12, Rehovot 76100, Israel
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7
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Han H, Jang J. Recent advances in biofabricated gut models to understand the gut-brain axis in neurological diseases. FRONTIERS IN MEDICAL TECHNOLOGY 2022; 4:931411. [PMID: 36188186 PMCID: PMC9515506 DOI: 10.3389/fmedt.2022.931411] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2022] [Accepted: 08/22/2022] [Indexed: 12/02/2022] Open
Abstract
Increasing evidence has accumulated that gut microbiome dysbiosis could be linked to neurological diseases, including both neurodegenerative and psychiatric diseases. With the high prevalence of neurological diseases, there is an urgent need to elucidate the underlying mechanisms between the microbiome, gut, and brain. However, the standardized aniikmal models for these studies have critical disadvantages for their translation into clinical application, such as limited physiological relevance due to interspecies differences and difficulty interpreting causality from complex systemic interactions. Therefore, alternative in vitro gut–brain axis models are highly required to understand their related pathophysiology and set novel therapeutic strategies. In this review, we outline state-of-the-art biofabrication technologies for modeling in vitro human intestines. Existing 3D gut models are categorized according to their topographical and anatomical similarities to the native gut. In addition, we deliberate future research directions to develop more functional in vitro intestinal models to study the gut–brain axis in neurological diseases rather than simply recreating the morphology.
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Affiliation(s)
- Hohyeon Han
- School of Interdisciplinary Bioscience and Bioengineering, Pohang University of Science and Technology (POSTECH), Pohang, South Korea
| | - Jinah Jang
- School of Interdisciplinary Bioscience and Bioengineering, Pohang University of Science and Technology (POSTECH), Pohang, South Korea
- Department of Mechanical Engineering, Pohang University of Science and Technology (POSTECH), Pohang, South Korea
- Department of Convergence IT Engineering, Pohang University of Science and Technology (POSTECH), Pohang, South Korea
- Institute of Convergence Science, Yonsei University, Seoul, South Korea
- Correspondence: Jinah Jang
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8
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Lok KH, Wareham NJ, Nair RS, How CW, Chuah LH. Revisiting the concept of incretin and enteroendocrine L-cells as type 2 diabetes mellitus treatment. Pharmacol Res 2022; 180:106237. [PMID: 35487405 PMCID: PMC7614293 DOI: 10.1016/j.phrs.2022.106237] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/08/2022] [Revised: 04/08/2022] [Accepted: 04/22/2022] [Indexed: 12/19/2022]
Abstract
The significant growth in type 2 diabetes mellitus (T2DM) prevalence strikes a common threat to the healthcare and economic systems globally. Despite the availability of several anti-hyperglycaemic agents in the market, none can offer T2DM remission. These agents include the prominent incretin-based therapy such as glucagon-like peptide-1 receptor (GLP-1R) agonists and dipeptidyl peptidase-4 inhibitors that are designed primarily to promote GLP-1R activation. Recent interest in various therapeutically useful gastrointestinal hormones in T2DM and obesity has surged with the realisation that enteroendocrine L-cells modulate the different incretins secretion and glucose homeostasis, reflecting the original incretin definition. Targeting L-cells offers promising opportunities to mimic the benefits of bariatric surgery on glucose homeostasis, bodyweight management, and T2DM remission. Revising the fundamental incretin theory is an essential step for therapeutic development in this area. Therefore, the present review explores enteroendocrine L-cell hormone expression, the associated nutrient-sensing mechanisms, and other physiological characteristics. Subsequently, enteroendocrine L-cell line models and the latest L-cell targeted therapies are reviewed critically in this paper. Bariatric surgery, pharmacotherapy and new paradigm of L-cell targeted pharmaceutical formulation are discussed here, offering both clinician and scientist communities a new common interest to push the scientific boundary in T2DM therapy.
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Affiliation(s)
- Kok-Hou Lok
- School of Pharmacy, Monash University Malaysia, Bandar Sunway, 47500 Subang Jaya, Selangor, Malaysia.
| | - Nicholas J Wareham
- School of Pharmacy, Monash University Malaysia, Bandar Sunway, 47500 Subang Jaya, Selangor, Malaysia; MRC Epidemiology Unit, University of Cambridge, Institute of Metabolic Science, Cambridge, UK.
| | - Rajesh Sreedharan Nair
- School of Pharmacy, Monash University Malaysia, Bandar Sunway, 47500 Subang Jaya, Selangor, Malaysia.
| | - Chee Wun How
- School of Pharmacy, Monash University Malaysia, Bandar Sunway, 47500 Subang Jaya, Selangor, Malaysia.
| | - Lay-Hong Chuah
- School of Pharmacy, Monash University Malaysia, Bandar Sunway, 47500 Subang Jaya, Selangor, Malaysia.
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9
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Buchanan KL, Rupprecht LE, Kaelberer MM, Sahasrabudhe A, Klein ME, Villalobos JA, Liu WW, Yang A, Gelman J, Park S, Anikeeva P, Bohórquez DV. The preference for sugar over sweetener depends on a gut sensor cell. Nat Neurosci 2022; 25:191-200. [PMID: 35027761 PMCID: PMC8825280 DOI: 10.1038/s41593-021-00982-7] [Citation(s) in RCA: 93] [Impact Index Per Article: 31.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2021] [Accepted: 11/09/2021] [Indexed: 12/18/2022]
Abstract
Guided by gut sensory cues, humans and animals prefer nutritive sugars over non-caloric sweeteners, but how the gut steers such preferences remains unknown. In the intestine, neuropod cells synapse with vagal neurons to convey sugar stimuli to the brain within seconds. Here, we found that cholecystokinin (CCK)-labeled duodenal neuropod cells differentiate and transduce luminal stimuli from sweeteners and sugars to the vagus nerve using sweet taste receptors and sodium glucose transporters. The two stimulus types elicited distinct neural pathways: while sweetener stimulated purinergic neurotransmission, sugar stimulated glutamatergic neurotransmission. To probe the contribution of these cells to behavior, we developed optogenetics for the gut lumen by engineering a flexible fiberoptic. We showed that preference for sugar over sweetener in mice depends on neuropod cell glutamatergic signaling. By swiftly discerning the precise identity of nutrient stimuli, gut neuropod cells serve as the entry point to guide nutritive choices. Buchanan, Rupprecht, Kaelberer and colleagues show that the preference for sugar over sweetener in mice depends on gut neuropod cells. Akin to other sensor cells, neuropod cells swiftly communicate the precise identity of stimuli to drive food choices.
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Affiliation(s)
- Kelly L Buchanan
- Laboratory of Gut Brain Neurobiology, Duke University, Durham, NC, USA.,Duke University School of Medicine, Durham, NC, USA
| | - Laura E Rupprecht
- Laboratory of Gut Brain Neurobiology, Duke University, Durham, NC, USA.,Department of Medicine, Duke University, Durham, NC, USA
| | - M Maya Kaelberer
- Laboratory of Gut Brain Neurobiology, Duke University, Durham, NC, USA.,Department of Medicine, Duke University, Durham, NC, USA
| | - Atharva Sahasrabudhe
- McGovern Institute for Brain Research, Massachusetts Institute of Technology, Cambridge, MA, USA.,Research Laboratory of Electronics, Massachusetts Institute of Technology, Cambridge, MA, USA.,Department of Chemistry, Massachusetts Institute of Technology, Cambridge, MA, USA
| | - Marguerita E Klein
- Laboratory of Gut Brain Neurobiology, Duke University, Durham, NC, USA.,Department of Medicine, Duke University, Durham, NC, USA
| | - Jorge A Villalobos
- Laboratory of Gut Brain Neurobiology, Duke University, Durham, NC, USA.,Department of Medicine, Duke University, Durham, NC, USA
| | - Winston W Liu
- Laboratory of Gut Brain Neurobiology, Duke University, Durham, NC, USA.,Duke University School of Medicine, Durham, NC, USA.,Department of Neurobiology, Duke University, Durham, NC, USA
| | - Annabelle Yang
- Laboratory of Gut Brain Neurobiology, Duke University, Durham, NC, USA.,Trinity College of Arts & Sciences, Duke University, Durham, NC, USA
| | - Justin Gelman
- Laboratory of Gut Brain Neurobiology, Duke University, Durham, NC, USA.,Trinity College of Arts & Sciences, Duke University, Durham, NC, USA
| | - Seongjun Park
- Research Laboratory of Electronics, Massachusetts Institute of Technology, Cambridge, MA, USA.,Department of Bio and Brain Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, Republic of Korea
| | - Polina Anikeeva
- McGovern Institute for Brain Research, Massachusetts Institute of Technology, Cambridge, MA, USA.,Research Laboratory of Electronics, Massachusetts Institute of Technology, Cambridge, MA, USA.,Departments of Materials Science & Engineering and Brain & Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, MA, USA
| | - Diego V Bohórquez
- Laboratory of Gut Brain Neurobiology, Duke University, Durham, NC, USA. .,Department of Medicine, Duke University, Durham, NC, USA. .,Department of Neurobiology, Duke University, Durham, NC, USA. .,Duke Institute for Brain Sciences, Duke University, Durham, NC, USA. .,MSRB-I, room 221A, 203 Research Drive, Durham, NC, USA.
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10
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Schmid C, Brockhoff A, Shoshan-Galeczki YB, Kranz M, Stark TD, Erkaya R, Meyerhof W, Niv MY, Dawid C, Hofmann T. Comprehensive structure-activity-relationship studies of sensory active compounds in licorice (Glycyrrhiza glabra). Food Chem 2021; 364:130420. [PMID: 34182369 DOI: 10.1016/j.foodchem.2021.130420] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2021] [Revised: 06/16/2021] [Accepted: 06/17/2021] [Indexed: 11/26/2022]
Abstract
Licorice saponins, the main constituents of Glycyrrhiza glabra L. roots, are highly appreciated by the consumer for their pleasant sweet and long lasting licorice taste. The objective of the present study was to understand the molecular features that contribute to bitter, sweet and licorice sensation of licorice roots, and whether individual compounds elicit more than one of these sensations. Therefore, a sensomics approach was conducted, followed by purification of the compounds with highest sensory impact, and by synthesis as well as full characterization via HRESIMS, ESIMS/MS and 1D/2D-NMR experiments. This led to the discovery and structure determination of 28 sweet, bitter and licorice tasting key phytochemicals, including two unknown compounds. A combination of sensorial, cell-based and computational analysis revealed distinct structural features, such as spatial arrangement of functional groups in the triterpenoid E-ring, driving to different taste sensations and sweet receptor hTAS1R2/R3 stimulation.
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Affiliation(s)
- Christian Schmid
- Food Chemistry and Molecular Sensory Science, Technical University of Munich, Lise-Meitner-Str. 34, 85354 Freising, Germany
| | - Anne Brockhoff
- Department of Molecular Genetics, German Institute of Human Nutrition Potsdam-Rehbrücke (DIfE), Arthur-Scheunert-Allee 114-116, 14558 Nuthetal, Germany
| | - Yaron Ben Shoshan-Galeczki
- The Institute of Biochemistry, Food and Nutrition, The Robert H Smith Faculty of Agriculture, Food and Environment, The Hebrew University, 76100 Rehovot and The Fritz Haber Center for Molecular Dynamics, The Hebrew University, Jerusalem 91904, Israel
| | - Maximilian Kranz
- Food Chemistry and Molecular Sensory Science, Technical University of Munich, Lise-Meitner-Str. 34, 85354 Freising, Germany
| | - Timo D Stark
- Food Chemistry and Molecular Sensory Science, Technical University of Munich, Lise-Meitner-Str. 34, 85354 Freising, Germany
| | - Rukiye Erkaya
- Food Chemistry and Molecular Sensory Science, Technical University of Munich, Lise-Meitner-Str. 34, 85354 Freising, Germany
| | - Wolfgang Meyerhof
- German Institute of Human Nutrition Potsdam-Rehbruecke, Arthur-Scheunert-Allee 114-116, 14558 Nuthetal, Germany; Center for Integrative Physiology and Molecular Medicine, Saarland University, Kirrberger Straße 100, 66421 Homburg, Germany
| | - Masha Y Niv
- The Institute of Biochemistry, Food and Nutrition, The Robert H Smith Faculty of Agriculture, Food and Environment, The Hebrew University, 76100 Rehovot and The Fritz Haber Center for Molecular Dynamics, The Hebrew University, Jerusalem 91904, Israel
| | - Corinna Dawid
- Food Chemistry and Molecular Sensory Science, Technical University of Munich, Lise-Meitner-Str. 34, 85354 Freising, Germany.
| | - Thomas Hofmann
- Food Chemistry and Molecular Sensory Science, Technical University of Munich, Lise-Meitner-Str. 34, 85354 Freising, Germany.
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11
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Klockars A, Levine AS, Head MA, Perez-Leighton CE, Kotz CM, Olszewski PK. Impact of Gut and Metabolic Hormones on Feeding Reward. Compr Physiol 2021; 11:1425-1447. [PMID: 33577129 DOI: 10.1002/cphy.c190042] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Abstract
Ingestion of food activates a cascade of endocrine responses (thereby reflecting a contemporaneous feeding status) that include the release of hormones from the gastrointestinal (GI) tract, such as cholecystokinin (CCK), glucagonlike peptide YY (PYY), peptide PP, and oleoylethanolamide, as well as suppression of ghrelin secretion. The pancreas and adipose tissue, on the other hand, release hormones that serve as a measure of the current metabolic state or the long-term energy stores, that is, insulin, leptin, and adiponectin. It is well known and intuitively understandable that these hormones target either directly (by crossing the blood-brain barrier) or indirectly (e.g., via vagal input) the "homeostatic" brainstem-hypothalamic pathways involved in the regulation of appetite. The current article focuses on yet another target of the metabolic and GI hormones that is critical in inducing changes in food intake, namely, the reward system. We discuss the physiological basis of this functional interaction, its importance in the control of appetite, and the impact that disruption of this crosstalk has on energy intake in select physiological and pathophysiological states. We conclude that metabolic and GI hormones have a capacity to strengthen or weaken a response of the reward system to a given food, and thus, they are fundamental in ensuring that feeding reward is plastic and dependent on the energy status of the organism. © 2021 American Physiological Society. Compr Physiol 11:1425-1447, 2021.
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Affiliation(s)
- Anica Klockars
- Faculty of Science and Engineering, University of Waikato, Hamilton, New Zealand
| | - Allen S Levine
- Department of Food Science and Nutrition, University of Minnesota, St. Paul, Minnesota, USA
| | - Mitchell A Head
- Faculty of Science and Engineering, University of Waikato, Hamilton, New Zealand
| | | | - Catherine M Kotz
- Department of Food Science and Nutrition, University of Minnesota, St. Paul, Minnesota, USA.,Department of Integrative Biology and Physiology, Medical School, University of Minnesota, Minneapolis, Minnesota, USA
| | - Pawel K Olszewski
- Faculty of Science and Engineering, University of Waikato, Hamilton, New Zealand.,Department of Food Science and Nutrition, University of Minnesota, St. Paul, Minnesota, USA.,Department of Integrative Biology and Physiology, Medical School, University of Minnesota, Minneapolis, Minnesota, USA
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12
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Alsunni AA. Effects of Artificial Sweetener Consumption on Glucose Homeostasis and Its Association with Type 2 Diabetes and Obesity. Int J Gen Med 2020; 13:775-785. [PMID: 33116769 PMCID: PMC7547772 DOI: 10.2147/ijgm.s274760] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2020] [Accepted: 09/10/2020] [Indexed: 11/23/2022] Open
Abstract
Artificial sweeteners (ASs) are popular for their characteristic property of providing sweetness with few or no calories. They are frequently consumed to minimize energy intake and to combat obesity and its related adverse health effects. However, since their introduction, concerns have been raised regarding their safety. Extensive research has designed a number of studies to evaluate potential adverse effects, the top among them being interference with glucose homeostasis. Numerous studies have tried to prove that AS may contribute to the development of metabolic diseases including obesity and type 2 diabetes (T2D). The matter remains controversial and a favorite topic of research. The purpose of this review was to identify and discuss the published articles that have examined the effects of AS consumption on glucose homeostasis and its association with T2D and obesity. It was observed that studies have failed to present concrete evidence to establish a link between AS consumption and glucose homeostasis, obesity, or T2D. Most studies have flaws in the study design resulting in haphazard claims with no follow-up studies to confirm reliability. It is concluded that while it is not possible to claim that ASs are metabolically inert, at the moment the haphazard evidence is not enough to link their use with glucose metabolism, obesity or T2D. There is a need to design cohort and case-control studies with reliable sample sizes to establish a cause-effect relationship or to exclude claims of safety problems.
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Affiliation(s)
- Ahmed Abdulrahman Alsunni
- Department of Physiology, College of Medicine, Imam Abdulrahman Bin Faisal University, Dammam, Saudi Arabia
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13
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Huang WK, Xie C, Young RL, Zhao JB, Ebendorff-Heidepriem H, Jones KL, Rayner CK, Wu TZ. Development of innovative tools for investigation of nutrient-gut interaction. World J Gastroenterol 2020; 26:3562-3576. [PMID: 32742126 PMCID: PMC7366065 DOI: 10.3748/wjg.v26.i25.3562] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/15/2020] [Revised: 05/29/2020] [Accepted: 06/18/2020] [Indexed: 02/06/2023] Open
Abstract
The gastrointestinal tract is the key interface between the ingesta and the human body. There is wide recognition that the gastrointestinal response to nutrients or bioactive compounds, particularly the secretion of numerous hormones, is critical to the regulation of appetite, body weight and blood glucose. This concept has led to an increasing focus on "gut-based" strategies for the management of metabolic disorders, including type 2 diabetes and obesity. Understanding the underlying mechanisms and downstream effects of nutrient-gut interactions is fundamental to effective translation of this knowledge to clinical practice. To this end, an array of research tools and platforms have been developed to better understand the mechanisms of gut hormone secretion from enteroendocrine cells. This review discusses the evolution of in vitro and in vivo models and the integration of innovative techniques that will ultimately enable the development of novel therapies for metabolic diseases.
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Affiliation(s)
- Wei-Kun Huang
- Adelaide Medical School, Centre of Research Excellence in Translating Nutritional Science to Good Health, the University of Adelaide, Adelaide, SA 5005, Australia
- Institute for Photonics and Advanced Sensing, School of Physical Sciences, University of Adelaide, Adelaide, SA 5005, Australia
- The ARC Centre of Excellence for Nanoscale BioPhotonics, Adelaide, SA 5005, Australia
| | - Cong Xie
- Adelaide Medical School, Centre of Research Excellence in Translating Nutritional Science to Good Health, the University of Adelaide, Adelaide, SA 5005, Australia
| | - Richard L Young
- Adelaide Medical School, Centre of Research Excellence in Translating Nutritional Science to Good Health, the University of Adelaide, Adelaide, SA 5005, Australia
- Diabetes, Nutrition and Gut Health, Lifelong Health, South Australia Health and Medical Research Institute, Adelaide, SA 5005, Australia
| | - Jiang-Bo Zhao
- Institute for Photonics and Advanced Sensing, School of Physical Sciences, University of Adelaide, Adelaide, SA 5005, Australia
- The ARC Centre of Excellence for Nanoscale BioPhotonics, Adelaide, SA 5005, Australia
| | - Heike Ebendorff-Heidepriem
- Institute for Photonics and Advanced Sensing, School of Physical Sciences, University of Adelaide, Adelaide, SA 5005, Australia
- The ARC Centre of Excellence for Nanoscale BioPhotonics, Adelaide, SA 5005, Australia
| | - Karen L Jones
- Adelaide Medical School, Centre of Research Excellence in Translating Nutritional Science to Good Health, the University of Adelaide, Adelaide, SA 5005, Australia
| | - Christopher K Rayner
- Adelaide Medical School, Centre of Research Excellence in Translating Nutritional Science to Good Health, the University of Adelaide, Adelaide, SA 5005, Australia
- Department of Gastroenterology and Hepatology, Royal Adelaide Hospital, Adelaide, SA 5000, Australia
| | - Tong-Zhi Wu
- Adelaide Medical School, Centre of Research Excellence in Translating Nutritional Science to Good Health, the University of Adelaide, Adelaide, SA 5005, Australia
- Department of Endocrinology, Zhongda Hospital, Institute of Diabetes, School of Medicine, Southeast University, Nanjing 210009, Jiangsu Province, China
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14
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Current Progress in Understanding the Structure and Function of Sweet Taste Receptor. J Mol Neurosci 2020; 71:234-244. [PMID: 32607758 DOI: 10.1007/s12031-020-01642-4] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2019] [Accepted: 06/19/2020] [Indexed: 10/24/2022]
Abstract
The sweet taste receptor, which was identified approximately 20 years ago, mediates sweet taste recognition in humans and other vertebrates. With the development of genomics, metabonomics, structural biology, evolutionary biology, physiology, and neuroscience, as well as technical advances in these areas, our understanding of this important protein has resulted in substantial progress. This article reviews the structure, function, genetics, and evolution of the sweet taste receptor and offers meaningful insights into this G protein-coupled receptor, which may be helpful guidances for personalized feeding, diet, and medicine. Prospective directions for research on sweet taste receptors have also been proposed.
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15
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Effects of Non-nutritive Sweeteners on Sweet Taste Processing and Neuroendocrine Regulation of Eating Behavior. Curr Nutr Rep 2020; 9:278-289. [PMID: 32588329 DOI: 10.1007/s13668-020-00323-3] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
PURPOSE OF REVIEW Non-nutritive sweeteners (NNS) are increasingly used as a replacement for nutritive sugars as means to quench the desire for "sweets" while contributing few or no dietary calories. However, there is concern that NNS may uncouple the evolved relationship between sweet taste and post-ingestive neuroendocrine signaling. In this review, we examine the effects of NNS exposure on neural and peripheral systems in humans. RECENT FINDINGS NNS exposure during early development may influence sweet taste preferences, and NNS consumption might increase motivation for sweet foods. Neuroimaging studies provide evidence that NNS elicit differential neuronal responsivity in areas related to reward and satiation, compared with caloric sweeteners. Findings are heterogenous regarding whether NNS affect physiological responses. Additional studies are warranted regarding the consequences of NNS on metabolic outcomes and neuroendocrine pathways. Given the widespread popularity of NNS, future studies are essential to establish their role in long-term health.
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16
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Xie SZ, Yang G, Jiang XM, Qin DY, Li QM, Zha XQ, Pan LH, Jin CS, Luo JP. Polygonatum cyrtonema Hua Polysaccharide Promotes GLP-1 Secretion from Enteroendocrine L-Cells through Sweet Taste Receptor-Mediated cAMP Signaling. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2020; 68:6864-6872. [PMID: 32456438 DOI: 10.1021/acs.jafc.0c02058] [Citation(s) in RCA: 45] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/11/2023]
Abstract
Glucagon-like peptide-1 (GLP-1) secreted from enteroendocrine L-cells is a pleiotropic hormone with beneficial potential related to islet function, diet control, glucose homeostasis, inflammation relief, and cardiovascular protection. The present study aimed at investigating the effect of Polygonatum cyrtonema polysaccharide (PCP) after structural identification on GLP-1 secretion and the possible mechanism involved in the PCP-stimulated secretion of GLP-1. It was found that GLP-1 secretion was effectively promoted (p < 0.01) by PCP both in rats with oral administration for 5 weeks (13.9 ± 0.3-35.8 ± 0.3 pmol/L) and ileal administration within 2 h (13.6 ± 0.4-34.1 ± 1.1 pmol/L) and in enteroendocrine NCI-H716 cells with direct stimulation within 24 h (2.05 ± 0.3-20.7 ± 0.2 pmol/L). The sweet taste receptor T1R2/T1R3 was identified to be essential for NCI-H716 cells to directly recognize PCP. The intervention experiments showed that PCP-stimulated GLP-1 secretion was significantly depressed (p < 0.01) not only by antibodies, siRNA, and the inhibitor of T1R2/T1R3 but also by an adenylate cyclase inhibitor. These results suggest that PCP stimulates GLP-1 secretion from enteroendocrine cells possibly through activation of the T1R2/T1R3-mediated cAMP signaling pathway.
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Affiliation(s)
- Song-Zi Xie
- School of Food and Biological Engineering, Hefei University of Technology, Hefei 230009, China
- College of Pharmacy, Anhui University of Chinese Medicine, Hefei, Anhui 230012, China
| | - Guang Yang
- School of Food and Biological Engineering, Hefei University of Technology, Hefei 230009, China
| | - Xian-Min Jiang
- School of Food and Biological Engineering, Hefei University of Technology, Hefei 230009, China
| | - Dan-Yang Qin
- School of Food and Biological Engineering, Hefei University of Technology, Hefei 230009, China
| | - Qiang-Ming Li
- School of Food and Biological Engineering, Hefei University of Technology, Hefei 230009, China
| | - Xue-Qiang Zha
- School of Food and Biological Engineering, Hefei University of Technology, Hefei 230009, China
| | - Li-Hua Pan
- School of Food and Biological Engineering, Hefei University of Technology, Hefei 230009, China
| | - Chuan-Shan Jin
- College of Pharmacy, Anhui University of Chinese Medicine, Hefei, Anhui 230012, China
| | - Jian-Ping Luo
- School of Food and Biological Engineering, Hefei University of Technology, Hefei 230009, China
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17
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Hunter SR, Reister EJ, Cheon E, Mattes RD. Low Calorie Sweeteners Differ in Their Physiological Effects in Humans. Nutrients 2019; 11:E2717. [PMID: 31717525 PMCID: PMC6893706 DOI: 10.3390/nu11112717] [Citation(s) in RCA: 44] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2019] [Revised: 11/04/2019] [Accepted: 11/06/2019] [Indexed: 12/13/2022] Open
Abstract
Low calorie sweeteners (LCS) are prevalent in the food supply for their primary functional property of providing sweetness with little or no energy. Though tested for safety individually, there has been extremely limited work on the efficacy of each LCS. It is commonly assumed all LCS act similarly in their behavioral and physiological effects. However, each LCS has its own chemical structure that influences its metabolism, making each LCS unique in its potential effects on body weight, energy intake, and appetite. LCS may have different behavioral and physiological effects mediated at the sweet taste receptor, in brain activation, with gut hormones, at the microbiota and on appetitive responses. Further elucidation of the unique effects of the different commercially available LCS may hold important implications for recommendations about their use for different health outcomes.
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Affiliation(s)
| | | | | | - Richard D. Mattes
- Department of Nutrition Science, Purdue University, West Lafayette, IN 47907, USA; (S.R.H.); (E.J.R.); (E.C.)
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18
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Sarnelli G, Annunziata G, Magno S, Oriolo C, Savastano S, Colao A. Taste and the Gastrointestinal tract: from physiology to potential therapeutic target for obesity. INTERNATIONAL JOURNAL OF OBESITY SUPPLEMENTS 2019; 9:1-9. [PMID: 31391920 DOI: 10.1038/s41367-019-0012-6] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/25/2023]
Abstract
Flavor is the combination of gustatory, olfactory and trigeminal sensations, representing the three main sensory pathways that allow detecting environmental chemical substances. Taste, in particular, is a complex chemosensory path that allows identification of substances present in ingested foods and beverages. In this manuscript, we propose a conceptual roadmap from aspects related to the evolution and the physiological role of taste, up to the current knowledge about its implication in the modulation of a healthy state, or obesity. More specifically, we focused on the role of stimulation of taste receptors in releasing gut hormones (also known as enterohormones), and their effects on the regulation of food intake, by inducing satiety, either by locally acting (in the gastrointestinal tract), or centrally (in the brain). Recent evidence demonstrated that some enterohormones are able to modulate gastrointestinal motility, thus affecting an orexigenic responses in the central nervous system. In keeping with this, we discuss the ability of the gustatory system to be a final checkpoint control for food intake regulation, and we speculate about taste perception manipulation in the management of obesity.
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Affiliation(s)
- Giovanni Sarnelli
- 1Department of Clinical Medicine and Surgery, Division of Gastroenterology, University of Naples Federico II, Naples, Italy
| | | | - Silvia Magno
- Obesity Center at the Endocrinology Unit, Department of Clinical and Experimental Medicine, Pisa, Italy
| | - Claudia Oriolo
- 4Endocrinology Unit, Medical Department of Care Continuity and Disability, University of Bologna, Bologna, Italy
| | - Silvia Savastano
- 5Dipartimento di Medicina Clinica e Chirurgia, Unit of Endocrinology, Federico II University Medical School of Naples, Napoli, Italy
| | - Annamaria Colao
- 5Dipartimento di Medicina Clinica e Chirurgia, Unit of Endocrinology, Federico II University Medical School of Naples, Napoli, Italy
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19
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Zopun M, Lieder B, Holik AK, Ley JP, Hans J, Somoza V. Noncaloric Sweeteners Induce Peripheral Serotonin Secretion via the T1R3-Dependent Pathway in Human Gastric Parietal Tumor Cells (HGT-1). JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2018; 66:7044-7053. [PMID: 29874909 DOI: 10.1021/acs.jafc.8b02071] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/21/2023]
Abstract
The role of sweet taste in energy intake and satiety regulation is still controversial. Noncaloric artificial sweeteners (NCSs) are thought to help reduce energy intake, although little is known about their impact on the satiating neurotransmitter serotonin (5-HT). In the gastrointestinal (GI) tract, 5-HT regulates gastric acid secretion and gastric motility, both part of the complex network of mechanisms regulating food intake and satiety. This study demonstrated a stimulating impact compared to controls (100%) on 5-HT release in human gastric tumor cells (HGT-1) by the NCSs cyclamate (50 mM, 157% ± 6.3%), acesulfame potassium (Ace K, 50 mM, 197% ± 8.6%), saccharin (50 mM, 147% ± 6.7%), sucralose (50 mM, 194% ± 11%), and neohesperidin dihydrochalcone (NHDC, 1 mM, 201% ± 13%). Although these effects were not associated with the sweet taste intensity of the NCSs tested, involvement of the sweet receptor subunit T1R3 in the NCS-evoked response was demonstrated by mRNA expression of TAS1R3, co-incubation experiments using the T1R3 receptor antagonist lactisole, and a TAS1R3 siRNA knockdown approach. Analysis of the downstream signaling revealed activation of the cAMP/ERK/Ca2+ cascade. Co-treatment experiments with 10 mM glucose enhanced the 5-HT release induced by cyclamate, Ace K, saccharin, and sucralose, thereby supporting the enhancing effect of glucose on a NCS-mediated response. Overall, the results obtained identify NCSs as potent inducers of 5-HT release via T1R3 in human gastric parietal cells in culture and warrant in vivo studies to demonstrate their efficacy.
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Affiliation(s)
- Muhammet Zopun
- Department of Physiological Chemistry, Faculty of Chemistry , University of Vienna , Althanstraße 14 , Vienna 1090 , Austria
| | - Barbara Lieder
- Department of Physiological Chemistry, Faculty of Chemistry , University of Vienna , Althanstraße 14 , Vienna 1090 , Austria
- Christian Doppler Laboratory for Taste Research, Faculty of Chemistry , University of Vienna , Althanstraße 14 , Vienna 1090 , Austria
| | - Ann-Katrin Holik
- Department of Physiological Chemistry, Faculty of Chemistry , University of Vienna , Althanstraße 14 , Vienna 1090 , Austria
| | - Jakop P Ley
- Symrise AG , Mühlenfeldstraße 1 , 37603 Holzminden , Germany
| | - Joachim Hans
- Symrise AG , Mühlenfeldstraße 1 , 37603 Holzminden , Germany
| | - Veronika Somoza
- Department of Physiological Chemistry, Faculty of Chemistry , University of Vienna , Althanstraße 14 , Vienna 1090 , Austria
- Christian Doppler Laboratory for Bioactive Aroma Compounds, Faculty of Chemistry , University of Vienna , Althanstraße 14 , Vienna 1090 , Austria
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20
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Zopun M, Liszt KI, Stoeger V, Behrens M, Redel U, Ley JP, Hans J, Somoza V. Human Sweet Receptor T1R3 is Functional in Human Gastric Parietal Tumor Cells (HGT-1) and Modulates Cyclamate and Acesulfame K-Induced Mechanisms of Gastric Acid Secretion. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2018; 66:4842-4852. [PMID: 29665689 DOI: 10.1021/acs.jafc.8b00658] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/08/2023]
Abstract
The noncaloric sweeteners (NCSs) cyclamate (Cycl) and acesulfame K (AceK) are widely added to foods and beverages. Little is known about their impact on gastric acid secretion (GAS), which is stimulated by dietary protein and bitter-tasting compounds. Since Cycl and AceK have a bitter off taste in addition to their sweet taste, we hypothesized they modulate mechanisms of GAS in human gastric parietal cells (HGT-1). HGT-1 cells were exposed to sweet tastants (50 mM of glucose, d-threonine, Cycl, or AceK) and analyzed for their intracellular pH index (IPX), as an indicator of proton secretion by means of a pH-sensitive dye, and for mRNA levels of GAS-associated genes by RT-qPCR. Since the NCSs act via the sweet taste-sensing receptor T1R2/T1R3, mRNA expression of the corresponding genes was analyzed in addition to immunocytochemical localization of the T1R2 and T1R3 receptor proteins. Exposure of HGT-1 cells to AceK or d-threonine increased the IPX to 0.60 ± 0.05 and 0.80 ± 0.04 ( P ≤ 0.05), respectively, thereby indicating a reduced secretion of protons, whereas Cycl demonstrated the opposite effect with IPX values of -0.69 ± 0.08 ( P ≤ 0.05) compared to controls (IPX = 0). Cotreatment with the T1R3-inhibitor lactisole as well as a TAS1R3 siRNA knock-down approach reduced the impact of Cycl, AceK, and d-thr on proton release ( P ≤ 0.05), whereas cotreatment with 10 mM glucose enhanced the NCS-induced effect ( P ≤ 0.05). Overall, we demonstrated Cycl and AceK as modulators of proton secretion in HGT-1 cells and identified T1R3 as a key element in this response.
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Affiliation(s)
- Muhammet Zopun
- Faculty of Chemistry, Department of Physiological Chemistry , University of Vienna , Althanstraße 14 , Vienna 1090 , Austria
| | - Kathrin I Liszt
- Faculty of Chemistry, Christian Doppler Laboratory for Bioactive Aroma Compounds , University of Vienna , Althanstraße 14 , Vienna 1090 , Austria
| | - Verena Stoeger
- Faculty of Chemistry, Christian Doppler Laboratory for Bioactive Aroma Compounds , University of Vienna , Althanstraße 14 , Vienna 1090 , Austria
| | - Maik Behrens
- Department of Molecular Genetics , German Institute of Human Nutrition Potsdam-Rehbruecke , Arthur-Scheunert-Allee , 114-116 Nuthetal , Germany
| | - Ulrike Redel
- Department of Molecular Genetics , German Institute of Human Nutrition Potsdam-Rehbruecke , Arthur-Scheunert-Allee , 114-116 Nuthetal , Germany
| | - Jakob P Ley
- Symrise AG , Mühlenfeldstraße 1 , 37603 Holzminden , Germany
| | - Joachim Hans
- Symrise AG , Mühlenfeldstraße 1 , 37603 Holzminden , Germany
| | - Veronika Somoza
- Faculty of Chemistry, Department of Physiological Chemistry , University of Vienna , Althanstraße 14 , Vienna 1090 , Austria
- Faculty of Chemistry, Christian Doppler Laboratory for Bioactive Aroma Compounds , University of Vienna , Althanstraße 14 , Vienna 1090 , Austria
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21
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Paternoster S, Falasca M. Dissecting the Physiology and Pathophysiology of Glucagon-Like Peptide-1. Front Endocrinol (Lausanne) 2018; 9:584. [PMID: 30364192 PMCID: PMC6193070 DOI: 10.3389/fendo.2018.00584] [Citation(s) in RCA: 42] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/04/2018] [Accepted: 09/14/2018] [Indexed: 12/11/2022] Open
Abstract
An aging world population exposed to a sedentary life style is currently plagued by chronic metabolic diseases, such as type-2 diabetes, that are spreading worldwide at an unprecedented rate. One of the most promising pharmacological approaches for the management of type 2 diabetes takes advantage of the peptide hormone glucagon-like peptide-1 (GLP-1) under the form of protease resistant mimetics, and DPP-IV inhibitors. Despite the improved quality of life, long-term treatments with these new classes of drugs are riddled with serious and life-threatening side-effects, with no overall cure of the disease. New evidence is shedding more light over the complex physiology of GLP-1 in health and metabolic diseases. Herein, we discuss the most recent advancements in the biology of gut receptors known to induce the secretion of GLP-1, to bridge the multiple gaps into our understanding of its physiology and pathology.
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22
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Sweeteners as food additives in the XXI century: A review of what is known, and what is to come. Food Chem Toxicol 2017; 107:302-317. [DOI: 10.1016/j.fct.2017.06.046] [Citation(s) in RCA: 133] [Impact Index Per Article: 16.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2017] [Revised: 06/26/2017] [Accepted: 06/28/2017] [Indexed: 01/07/2023]
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23
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Riedel K, Sombroek D, Fiedler B, Siems K, Krohn M. Human cell-based taste perception - a bittersweet job for industry. Nat Prod Rep 2017; 34:484-495. [PMID: 28393162 DOI: 10.1039/c6np00123h] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/02/2023]
Abstract
Covering: 2000 to 2016On the molecular level humans sense food by a variety of specialized tissues which express sensory receptors to handle nutritive value. In general, this means the interplay of gustatory, olfactory, trigeminal and haptic sensation is translated into perception and leads, in terms of taste, to descriptions like sweet, bitter, salty, sour and umami. Further perceptions include astringent, cool, hot, prickle, lingering, kokumi and fatty to name predominant characterizations. It is still not fully understood how this plethora of impressions can be perceived by quite a limited number of receptors obviously being the initial compilers to judge palatability. However, since the discovery of mammalian taste receptors (TASRs) almost 30 years ago the use of taste receptors in cell-based screening campaigns is advancing in industrial approaches. The article will highlight the impacts and the limits of cell-based guided identification of taste modulators for food applications with an emphasis on sweet, bitter and savory taste as well as implications emerging from natural products.
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Affiliation(s)
- K Riedel
- BRAIN AG, Darmstädter Str. 34-36, 64673 Zwingenberg, Germany.
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24
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Grotz VL, Pi-Sunyer X, Porte D, Roberts A, Richard Trout J. A 12-week randomized clinical trial investigating the potential for sucralose to affect glucose homeostasis. Regul Toxicol Pharmacol 2017; 88:22-33. [PMID: 28502831 DOI: 10.1016/j.yrtph.2017.05.011] [Citation(s) in RCA: 49] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2017] [Revised: 05/05/2017] [Accepted: 05/10/2017] [Indexed: 10/19/2022]
Abstract
The discovery of gut sweet taste receptors has led to speculations that non-nutritive sweeteners, including sucralose, may affect glucose control. A double-blind, parallel, randomized clinical trial, reported here and previously submitted to regulatory agencies, helps to clarify the role of sucralose in this regard. This was primarily an out-patient study, with 4-week screening, 12-week test, and 4-week follow-up phases. Normoglycemic male volunteers (47) consumed ∼333.3 mg encapsulated sucralose or placebo 3x/day at mealtimes. HbA1c, fasting glucose, insulin, and C-peptide were measured weekly. OGTTs were conducted in-clinic overnight, following overnight fasting twice during screening phase, twice during test phase, and once at follow-up. Throughout the study, glucose, insulin, C-peptide and HbA1c levels were within normal range. No statistically significant differences between sucralose and placebo groups in change from baseline for fasting glucose, insulin, C-peptide and HbA1c, no clinically meaningful differences in time to peak levels or return towards basal levels in OGTTs, and no treatment group differences in mean glucose, insulin, or C-peptide AUC change from baseline were observed. The results of other relevant clinical trials and studies of gastrointestinal sweet taste receptors are compared to these findings. The collective evidence supports that sucralose has no effect on glycemic control.
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Affiliation(s)
- V Lee Grotz
- McNeil Nutritionals, Fort Washington, PA 19034, United States.
| | - Xavier Pi-Sunyer
- Department of Medicine, Division of Endocrinology, Columbia University College of Physicians and Surgeons, New York, NY 10025, United States.
| | - Daniel Porte
- Department of Medicine, Division of Endocrinology and Metabolism, University of California San Diego, San Diego, CA, United States; Department of Medicine, Endocrinology, Diabetes and Metabolism Section, VA San Diego Health Care System, San Diego, CA, United States.
| | - Ashley Roberts
- Food & Nutrition Group, Intertek Scientific & Regulatory Consultancy, Mississauga, Ontario, Canada.
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Steensels S, Vancleef L, Depoortere I. The Sweetener-Sensing Mechanisms of the Ghrelin Cell. Nutrients 2016; 8:E795. [PMID: 27941594 PMCID: PMC5188450 DOI: 10.3390/nu8120795] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2016] [Revised: 11/21/2016] [Accepted: 11/28/2016] [Indexed: 12/12/2022] Open
Abstract
Carbohydrate administration decreases plasma levels of the 'hunger hormone' ghrelin. The ghrelin cell is co-localized with the sweet taste receptor subunit, TAS1R3, and the gustatory G-protein, gustducin, both involved in the sensing of sweeteners by entero-endocrine cells. This study investigated the role of gustducin-mediated sweet taste receptor signaling on ghrelin secretion in a gastric ghrelinoma cell line, tissue segments and mice. The monosaccharide d-glucose and low-intensity sweetener oligofructose (OFS) decreased (p < 0.001) ghrelin secretion while the high-intensity sweetener sucralose increased (p < 0.001) ghrelin secretion in vitro. These effects were not mediated via the sweet taste receptor or glucose transporters (the sodium-dependent glucose cotransporter SGLT-1 and GLUT2). The effect of these compounds was mimicked ex vivo in gastric and jejunal segments from both wild type (WT) and α-gustducin knockout (α-gust-/-) mice. In vivo, the sensing of d-glucose was polarized since intragastric but not intravenous administration of d-glucose decreased (p < 0.05) ghrelin levels in an α-gustducin independent manner which involved inhibition of duodenal ghrelin release. In contrast, neither OFS nor sucralose affected ghrelin secretion in vivo. In conclusion, α-gustducin-mediated sweet taste receptor signaling does not play a functional role in the sensing of carbohydrates, or low- or high-intensity sweeteners by the ghrelin cell.
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Affiliation(s)
- Sandra Steensels
- Gut Peptide Lab, Translational Research Center for Gastrointestinal Disorders (TARGID), University of Leuven-KU Leuven, 3000 Leuven, Belgium.
| | - Laurien Vancleef
- Gut Peptide Lab, Translational Research Center for Gastrointestinal Disorders (TARGID), University of Leuven-KU Leuven, 3000 Leuven, Belgium.
| | - Inge Depoortere
- Gut Peptide Lab, Translational Research Center for Gastrointestinal Disorders (TARGID), University of Leuven-KU Leuven, 3000 Leuven, Belgium.
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Kohno D, Koike M, Ninomiya Y, Kojima I, Kitamura T, Yada T. Sweet Taste Receptor Serves to Activate Glucose- and Leptin-Responsive Neurons in the Hypothalamic Arcuate Nucleus and Participates in Glucose Responsiveness. Front Neurosci 2016; 10:502. [PMID: 27877104 PMCID: PMC5099526 DOI: 10.3389/fnins.2016.00502] [Citation(s) in RCA: 36] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2016] [Accepted: 10/21/2016] [Indexed: 01/04/2023] Open
Abstract
The hypothalamic feeding center plays an important role in energy homeostasis. In the feeding center, whole-body energy signals including hormones and nutrients are sensed, processed, and integrated. As a result, food intake and energy expenditure are regulated. Two types of glucose-sensing neurons exist in the hypothalamic arcuate nucleus (ARC): glucose-excited neurons and glucose-inhibited neurons. While some molecules are known to be related to glucose sensing in the hypothalamus, the mechanisms underlying glucose sensing in the hypothalamus are not fully understood. The sweet taste receptor is a heterodimer of taste type 1 receptor 2 (T1R2) and taste type 1 receptor 3 (T1R3) and senses sweet tastes. T1R2 and T1R3 are distributed in multiple organs including the tongue, pancreas, adipose tissue, and hypothalamus. However, the role of sweet taste receptors in the ARC remains to be clarified. To examine the role of sweet taste receptors in the ARC, cytosolic Ca2+ concentration ([Ca2+]i) in isolated single ARC neurons were measured using Fura-2 fluorescent imaging. An artificial sweetener, sucralose at 10−5–10−2 M dose dependently increased [Ca2+]i in 12–16% of ARC neurons. The sucralose-induced [Ca2+]i increase was suppressed by a sweet taste receptor inhibitor, gurmarin. The sucralose-induced [Ca2+]i increase was inhibited under an extracellular Ca2+-free condition and in the presence of an L-type Ca2+ channel blocker, nitrendipine. Sucralose-responding neurons were activated by high-concentration of glucose. This response to glucose was markedly suppressed by gurmarin. More than half of sucralose-responding neurons were activated by leptin but not ghrelin. Percentages of proopiomelanocortin (POMC) neurons among sucralose-responding neurons and sweet taste receptor expressing neurons were low, suggesting that majority of sucralose-responding neurons are non-POMC neurons. These data suggest that sweet taste receptor-mediated cellular activation mainly occurs on non-POMC leptin-responding neurons and contributes to glucose responding. Endogenous sweet molecules including glucose may regulate energy homeostasis through sweet taste receptors on glucose-and leptin-responsive neurons in the ARC.
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Affiliation(s)
- Daisuke Kohno
- Advanced Scientific Research Leaders Development Unit, Gunma UniversityMaebashi, Japan; Metabolic Signal Research Center, Institute for Molecular and Cellular Regulation, Gunma UniversityMaebashi, Japan
| | - Miho Koike
- Advanced Scientific Research Leaders Development Unit, Gunma University Maebashi, Japan
| | - Yuzo Ninomiya
- Division of Sensory Physiology, Research and Development Center for Taste and Odor Sensing, Kyushu UniversityFukuoka, Japan; Monell Chemical Senses CenterPhiladelphia, PA, USA
| | - Itaru Kojima
- Department of Cell Biology, Institute for Molecular and Cellular Regulation, Gunma University Maebashi, Japan
| | - Tadahiro Kitamura
- Metabolic Signal Research Center, Institute for Molecular and Cellular Regulation, Gunma University Maebashi, Japan
| | - Toshihiko Yada
- Division of Integrative Physiology, Department of Physiology, School of Medicine, Jichi Medical University Shimotsuke, Japan
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Abstract
PURPOSE OF REVIEW To summarize and illuminate the recent findings regarding gastroduodenal mucosal defense mechanisms and the specific biomolecules involved in regulating this process, such as glucagon-like peptides (GLPs). RECENT FINDINGS There has been a growing interest in luminal nutrient chemosensing and its physiological effects throughout the digestive system. From the ingestion of food in the oral cavity to the processing and absorption of nutrients in the intestines, nutrient chemosensing receptors signal the production and release of numerous bioactive peptides from enteroendocrine cells, such as the proglucagon-derived peptides. There has been a major emphasis on two proglucagon-derived peptides, namely GLP-1 and GLP-2, due to their apparent beneficial effect on gut structure, function, and on metabolic processes. As an incretin, GLP-1 not only enhances the effect and release of insulin on pancreatic βcells but also has been implicated in having trophic effects on the intestinal epithelium. In addition, GLP-2, the other major proglucagon-derived peptide, has potent intestinotrophic effects, such as increasing the rate of mucosal stem cell proliferation, mucosal blood flow, and fluid absorption, as well as augmenting the rate of duodenal bicarbonate secretion to improve gastric mucosal health and longevity. SUMMARY Understanding the mechanisms underlying nutrient chemosensing and how it relates to GLP release can further elucidate how the gut functions in response to cellular changes and disturbances. Furthermore, a more in-depth comprehension of GLP release and its tissue-specific effects will help improve the utility of GLP-1 and GLP-2 receptor agonists in clinical settings. This, in turn, should help patients suffering from intestinal failure, malabsorption, and mucosal injury.
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Medina J, Nakagawa Y, Nagasawa M, Fernandez A, Sakaguchi K, Kitaguchi T, Kojima I. Positive Allosteric Modulation of the Calcium-sensing Receptor by Physiological Concentrations of Glucose. J Biol Chem 2016; 291:23126-23135. [PMID: 27613866 DOI: 10.1074/jbc.m116.729863] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2016] [Indexed: 01/08/2023] Open
Abstract
The calcium-sensing receptor (CaSR) is activated by various cations, cationic compounds, and amino acids. In the present study we investigated the effect of glucose on CaSR in HEK293 cells stably expressing human CaSR (HEK-CaSR cells). When glucose concentration in the buffer was raised from 3 to 25 mm, a rapid elevation of cytoplasmic Ca2+ concentration ([Ca2+]c) was observed. This elevation was immediate and transient and was followed by a sustained decrease in [Ca2+]c The effect of glucose was detected at a concentration of 4 mm and reached its maximum at 5 mm 3-O-Methylglucose, a non-metabolizable analogue of glucose, reproduced the effect of glucose. Sucrose also induced an elevation of [Ca2+]c in HEK-CaSR cells. Similarly, sucralose was nearly as effective as glucose in inducing elevation of [Ca2+]c Glucose was not able to increase [Ca2+]c in the absence of extracellular Ca2+ The effect of glucose on [Ca2+]c was inhibited by NPS-2143, an allosteric inhibitor of CaSR. In addition, NPS-2143 also inhibited the [Ca2+]c responses to sucralose and sucrose. Glucose as well as sucralose decreased cytoplasmic cAMP concentration in HEK-CaSR cells. The reduction of cAMP induced by glucose was blocked by pertussis toxin. Likewise, sucralose reduced [cAMP]c Finally, glucose increased [Ca2+]c in PT-r parathyroid cells and in Madin-Darby canine kidney cells, both of which express endogenous CaSR. These results indicate that glucose acts as a positive allosteric modulator of CaSR.
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Affiliation(s)
- Johan Medina
- From the Institute for Molecular and Cellular Regulation, Gunma University, Maebashi 371-8512, Japan
| | - Yuko Nakagawa
- From the Institute for Molecular and Cellular Regulation, Gunma University, Maebashi 371-8512, Japan
| | - Masahiro Nagasawa
- From the Institute for Molecular and Cellular Regulation, Gunma University, Maebashi 371-8512, Japan
| | - Anny Fernandez
- From the Institute for Molecular and Cellular Regulation, Gunma University, Maebashi 371-8512, Japan
| | - Kazushige Sakaguchi
- Institute of Advanced Medicine, Wakayama Medical University, Wakayama 641-8509, Japan
| | - Tetsuya Kitaguchi
- Waseda Bioscience Research Institute in Singapore Singapore 138667, and.,Organization for University Research Initiatives, Waseda University, Tokyo 162-0041, Japan
| | - Itaru Kojima
- From the Institute for Molecular and Cellular Regulation, Gunma University, Maebashi 371-8512, Japan,
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Hsiao YH, Hsu CH, Chen C. A High-Throughput Automated Microfluidic Platform for Calcium Imaging of Taste Sensing. Molecules 2016; 21:E896. [PMID: 27399663 PMCID: PMC6273845 DOI: 10.3390/molecules21070896] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2016] [Revised: 07/01/2016] [Accepted: 07/06/2016] [Indexed: 12/30/2022] Open
Abstract
The human enteroendocrine L cell line NCI-H716, expressing taste receptors and taste signaling elements, constitutes a unique model for the studies of cellular responses to glucose, appetite regulation, gastrointestinal motility, and insulin secretion. Targeting these gut taste receptors may provide novel treatments for diabetes and obesity. However, NCI-H716 cells are cultured in suspension and tend to form multicellular aggregates, preventing high-throughput calcium imaging due to interferences caused by laborious immobilization and stimulus delivery procedures. Here, we have developed an automated microfluidic platform that is capable of trapping more than 500 single cells into microwells with a loading efficiency of 77% within two minutes, delivering multiple chemical stimuli and performing calcium imaging with enhanced spatial and temporal resolutions when compared to bath perfusion systems. Results revealed the presence of heterogeneity in cellular responses to the type, concentration, and order of applied sweet and bitter stimuli. Sucralose and denatonium benzoate elicited robust increases in the intracellular Ca(2+) concentration. However, glucose evoked a rapid elevation of intracellular Ca(2+) followed by reduced responses to subsequent glucose stimulation. Using Gymnema sylvestre as a blocking agent for the sweet taste receptor confirmed that different taste receptors were utilized for sweet and bitter tastes. This automated microfluidic platform is cost-effective, easy to fabricate and operate, and may be generally applicable for high-throughput and high-content single-cell analysis and drug screening.
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Affiliation(s)
- Yi-Hsing Hsiao
- Institute of Nanoengineering and Microsystems, National Tsing Hua University, Hsinchu 30013, Taiwan.
- Institute of Biomedical Engineering and Nanomedicine, National Health Research Institutes, Miaoli 35053, Taiwan.
| | - Chia-Hsien Hsu
- Institute of Nanoengineering and Microsystems, National Tsing Hua University, Hsinchu 30013, Taiwan.
- Institute of Biomedical Engineering and Nanomedicine, National Health Research Institutes, Miaoli 35053, Taiwan.
| | - Chihchen Chen
- Institute of Nanoengineering and Microsystems, National Tsing Hua University, Hsinchu 30013, Taiwan.
- Department of Power Mechanical Engineering, National Tsing Hua University, Hsinchu 30013, Taiwan.
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Kojima I, Nakagawa Y, Hamano K, Medina J, Li L, Nagasawa M. Glucose-Sensing Receptor T1R3: A New Signaling Receptor Activated by Glucose in Pancreatic β-Cells. Biol Pharm Bull 2016; 38:674-9. [PMID: 25947913 DOI: 10.1248/bpb.b14-00895] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Subunits of the sweet taste receptors T1R2 and T1R3 are expressed in pancreatic β-cells. Compared with T1R3, mRNA expression of T1R2 is considerably lower. At the protein level, expression of T1R2 is undetectable in β-cells. Accordingly, a major component of the sweet taste-sensing receptor in β-cells may be a homodimer of T1R3 rather than a heterodimer of T1R2/T1R3. Inhibition of this receptor by gurmarin or deletion of the T1R3 gene attenuates glucose-induced insulin secretion from β-cells. Hence the T1R3 homodimer functions as a glucose-sensing receptor (GSR) in pancreatic β-cells. When GSR is activated by the T1R3 agonist sucralose, elevation of intracellular ATP concentration ([ATP]i) is observed. Sucralose increases [ATP]i even in the absence of ambient glucose, indicating that sucralose increases [ATP]i not simply by activating glucokinase, a rate-limiting enzyme in the glycolytic pathway. In addition, sucralose augments elevation of [ATP]i induced by methylsuccinate, suggesting that sucralose activates mitochondrial metabolism. Nonmetabolizable 3-O-methylglucose also increases [ATP]i and knockdown of T1R3 attenuates elevation of [ATP]i induced by high concentration of glucose. Collectively, these results indicate that the T1R3 homodimer functions as a GSR; this receptor is involved in glucose-induced insulin secretion by activating glucose metabolism probably in mitochondria.
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Affiliation(s)
- Itaru Kojima
- Institute for Molecular & Cellular Regulation, Gunma University
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Kampmann K, Ueberberg S, Menge BA, Breuer TGK, Uhl W, Tannapfel A, Meier JJ. Abundance and turnover of GLP-1 producing L-cells in ileal mucosa are not different in patients with and without type 2 diabetes. Metabolism 2016; 65:84-91. [PMID: 26892519 DOI: 10.1016/j.metabol.2015.10.025] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/15/2015] [Revised: 10/01/2015] [Accepted: 10/18/2015] [Indexed: 12/16/2022]
Abstract
INTRODUCTION The gastrointestinal hormone GLP-1 is released from enteroendocrine L-cells and augments postprandial insulin secretion. In patients with type 2 diabetes, the incretin effect is markedly diminished. It is unclear, whether this is due to a reduction in the abundance of L-cells in the intestine. METHODS Ileal tissue samples from 10 patients with and 10 patients without diabetes that underwent surgery for the removal of colon tumors were included. Tissue sections were stained for GLP-1, Ki67, TUNEL and chromogranin A. RESULTS The number of L-cells was not different between patients with and without diabetes in either crypts (1.81±0.21% vs. 1.49±0.24%, respectively; p=0.31) or villi (1.07±0.16% vs. 0.83±0.10%, respectively; p=0.23). L-cell number was higher in crypts than in villi (p<0.0001). L-cell replication was detected rarely and not different between the groups. L-cell apoptosis was similar in patients with and without diabetes in both crypts (7.84±2.77% vs. 8.65±3.77%, p=0.85) and villi (4.48±2.89% vs. 8.62±4.64%, p=0.42). Chromogranin A staining was found in a subset of L-cells only. CONCLUSIONS Intestinal L-cell density is higher in crypts than in villi. Chromogranin A is not a prerequisite for GLP-1 production. L-cell density and turnover are not different between patients with and without diabetes. Thus, alterations in the number of GLP-1 producing cells do not explain the reduced incretin effect in patients with type 2 diabetes.
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Affiliation(s)
- Kirsten Kampmann
- Diabetes Division, St. Josef-Hospital, Ruhr-University Bochum, Gudrunstrasse 56, Bochum, 44791, Germany
| | - Sandra Ueberberg
- Diabetes Division, St. Josef-Hospital, Ruhr-University Bochum, Gudrunstrasse 56, Bochum, 44791, Germany
| | - Bjoern A Menge
- Diabetes Division, St. Josef-Hospital, Ruhr-University Bochum, Gudrunstrasse 56, Bochum, 44791, Germany
| | - Thomas G K Breuer
- Diabetes Division, St. Josef-Hospital, Ruhr-University Bochum, Gudrunstrasse 56, Bochum, 44791, Germany
| | - Waldemar Uhl
- Department of Surgery, St. Josef-Hospital, Ruhr-University Bochum, Gudrunstrasse 56, Bochum, 44791, Germany
| | - Andrea Tannapfel
- Institute of Pathology, Ruhr-University Bochum, Bürkle de la Camp-Platz 1, Bochum, 44789, Germany
| | - Juris J Meier
- Diabetes Division, St. Josef-Hospital, Ruhr-University Bochum, Gudrunstrasse 56, Bochum, 44791, Germany.
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Nakagawa Y, Nagasawa M, Medina J, Kojima I. Glucose Evokes Rapid Ca2+ and Cyclic AMP Signals by Activating the Cell-Surface Glucose-Sensing Receptor in Pancreatic β-Cells. PLoS One 2015; 10:e0144053. [PMID: 26630567 PMCID: PMC4667910 DOI: 10.1371/journal.pone.0144053] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2015] [Accepted: 11/12/2015] [Indexed: 12/21/2022] Open
Abstract
Glucose is a primary stimulator of insulin secretion in pancreatic β-cells. High concentration of glucose has been thought to exert its action solely through its metabolism. In this regard, we have recently reported that glucose also activates a cell-surface glucose-sensing receptor and facilitates its own metabolism. In the present study, we investigated whether glucose activates the glucose-sensing receptor and elicits receptor-mediated rapid actions. In MIN6 cells and isolated mouse β-cells, glucose induced triphasic changes in cytoplasmic Ca(2+) concentration ([Ca(2+)]c); glucose evoked an immediate elevation of [Ca(2+)]c, which was followed by a decrease in [Ca(2+)]c, and after a certain lag period it induced large oscillatory elevations of [Ca(2+)]c. Initial rapid peak and subsequent reduction of [Ca(2+)]c were independent of glucose metabolism and reproduced by a nonmetabolizable glucose analogue. These signals were also blocked by an inhibitor of T1R3, a subunit of the glucose-sensing receptor, and by deletion of the T1R3 gene. Besides Ca(2+), glucose also induced an immediate and sustained elevation of intracellular cAMP ([cAMP]c). The elevation of [cAMP]c was blocked by transduction of the dominant-negative Gs, and deletion of the T1R3 gene. These results indicate that glucose induces rapid changes in [Ca(2+)]c and [cAMP]c by activating the cell-surface glucose-sensing receptor. Hence, glucose generates rapid intracellular signals by activating the cell-surface receptor.
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Affiliation(s)
- Yuko Nakagawa
- Department of Cell Biology, Institute for Molecular & Cellular Regulation, Gunma University, Maebashi, Japan
| | - Masahiro Nagasawa
- Department of Cell Biology, Institute for Molecular & Cellular Regulation, Gunma University, Maebashi, Japan
| | - Johan Medina
- Department of Cell Biology, Institute for Molecular & Cellular Regulation, Gunma University, Maebashi, Japan
| | - Itaru Kojima
- Department of Cell Biology, Institute for Molecular & Cellular Regulation, Gunma University, Maebashi, Japan
- * E-mail:
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Mace OJ, Tehan B, Marshall F. Pharmacology and physiology of gastrointestinal enteroendocrine cells. Pharmacol Res Perspect 2015. [PMID: 26213627 PMCID: PMC4506687 DOI: 10.1002/prp2.155] [Citation(s) in RCA: 52] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
Gastrointestinal (GI) polypeptides are secreted from enteroendocrine cells (EECs). Recent technical advances and the identification of endogenous and synthetic ligands have enabled exploration of the pharmacology and physiology of EECs. Enteroendocrine signaling pathways stimulating hormone secretion involve multiple nutrient transporters and G protein-coupled receptors (GPCRs), which are activated simultaneously under prevailing nutrient conditions in the intestine following a meal. The majority of studies investigate hormone secretion from EECs in response to single ligands and although the mechanisms behind how individual signaling pathways generate a hormonal output have been well characterized, our understanding of how these signaling pathways converge to generate a single hormone secretory response is still in its infancy. However, a picture is beginning to emerge of how nutrients and full, partial, or allosteric GPCR ligands differentially regulate the enteroendocrine system and its interaction with the enteric and central nervous system. So far, activation of multiple pathways underlies drug discovery efforts to harness the therapeutic potential of the enteroendocrine system to mimic the phenotypic changes observed in patients who have undergone Roux-en-Y gastric surgery. Typically obese patients exhibit ∼30% weight loss and greater than 80% of obese diabetics show remission of diabetes. Targeting combinations of enteroendocrine signaling pathways that work synergistically may manifest with significant, differentiated EEC secretory efficacy. Furthermore, allosteric modulators with their increased selectivity, self-limiting activity, and structural novelty may translate into more promising enteroendocrine drugs. Together with the potential to bias enteroendocrine GPCR signaling and/or to activate multiple divergent signaling pathways highlights the considerable range of therapeutic possibilities available. Here, we review the pharmacology and physiology of the EEC system.
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Affiliation(s)
- O J Mace
- Heptares Therapeutics Ltd BioPark, Broadwater Road, Welwyn Garden City, AL7 3AX, United Kingdom
| | - B Tehan
- Heptares Therapeutics Ltd BioPark, Broadwater Road, Welwyn Garden City, AL7 3AX, United Kingdom
| | - F Marshall
- Heptares Therapeutics Ltd BioPark, Broadwater Road, Welwyn Garden City, AL7 3AX, United Kingdom
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Hamano K, Nakagawa Y, Ohtsu Y, Li L, Medina J, Tanaka Y, Masuda K, Komatsu M, Kojima I. Lactisole inhibits the glucose-sensing receptor T1R3 expressed in mouse pancreatic β-cells. J Endocrinol 2015; 226:57-66. [PMID: 25994004 DOI: 10.1530/joe-15-0102] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 05/20/2015] [Indexed: 11/08/2022]
Abstract
Glucose activates the glucose-sensing receptor T1R3 and facilitates its own metabolism in pancreatic β-cells. An inhibitor of this receptor would be helpful in elucidating the physiological function of the glucose-sensing receptor. The present study was conducted to examine whether or not lactisole can be used as an inhibitor of the glucose-sensing receptor. In MIN6 cells, in a dose-dependent manner, lactisole inhibited insulin secretion induced by sweeteners, acesulfame-K, sucralose and glycyrrhizin. The IC50 was ∼4 mmol/l. Lactisole attenuated the elevation of cytoplasmic Ca2+ concentration ([Ca2+]c) evoked by sucralose and acesulfame-K but did not affect the elevation of intracellular cAMP concentration ([cAMP]c) induced by these sweeteners. Lactisole also inhibited the action of glucose in MIN6 cells. Thus, lactisole significantly reduced elevations of intracellular [NADH] and intracellular [ATP] induced by glucose, and also inhibited glucose-induced insulin secretion. To further examine the effect of lactisole on T1R3, we prepared HEK293 cells stably expressing mouse T1R3. In these cells, sucralose elevated both [Ca2+]c and [cAMP]c. Lactisole attenuated the sucralose-induced increase in [Ca2+]c but did not affect the elevation of [cAMP]c. Finally, lactisole inhibited insulin secretion induced by a high concentration of glucose in mouse islets. These results indicate that the mouse glucose-sensing receptor was inhibited by lactisole. Lactisole may be useful in assessing the role of the glucose-sensing receptor in mouse pancreatic β-cells.
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Affiliation(s)
- Kunihisa Hamano
- Institute for Molecular and Cellular RegulationGunma University, Maebashi 371-8512, JapanDepartment of General MedicineNational Defense Medical College, Tokorozawa, JapanSuntory Institute for Bioorganic ResearchOsaka, JapanDepartment of Internal MedicineShinshu University School of Medicine, Matsumoto, Japan Institute for Molecular and Cellular RegulationGunma University, Maebashi 371-8512, JapanDepartment of General MedicineNational Defense Medical College, Tokorozawa, JapanSuntory Institute for Bioorganic ResearchOsaka, JapanDepartment of Internal MedicineShinshu University School of Medicine, Matsumoto, Japan
| | - Yuko Nakagawa
- Institute for Molecular and Cellular RegulationGunma University, Maebashi 371-8512, JapanDepartment of General MedicineNational Defense Medical College, Tokorozawa, JapanSuntory Institute for Bioorganic ResearchOsaka, JapanDepartment of Internal MedicineShinshu University School of Medicine, Matsumoto, Japan
| | - Yoshiaki Ohtsu
- Institute for Molecular and Cellular RegulationGunma University, Maebashi 371-8512, JapanDepartment of General MedicineNational Defense Medical College, Tokorozawa, JapanSuntory Institute for Bioorganic ResearchOsaka, JapanDepartment of Internal MedicineShinshu University School of Medicine, Matsumoto, Japan
| | - Longfei Li
- Institute for Molecular and Cellular RegulationGunma University, Maebashi 371-8512, JapanDepartment of General MedicineNational Defense Medical College, Tokorozawa, JapanSuntory Institute for Bioorganic ResearchOsaka, JapanDepartment of Internal MedicineShinshu University School of Medicine, Matsumoto, Japan
| | - Johan Medina
- Institute for Molecular and Cellular RegulationGunma University, Maebashi 371-8512, JapanDepartment of General MedicineNational Defense Medical College, Tokorozawa, JapanSuntory Institute for Bioorganic ResearchOsaka, JapanDepartment of Internal MedicineShinshu University School of Medicine, Matsumoto, Japan
| | - Yuji Tanaka
- Institute for Molecular and Cellular RegulationGunma University, Maebashi 371-8512, JapanDepartment of General MedicineNational Defense Medical College, Tokorozawa, JapanSuntory Institute for Bioorganic ResearchOsaka, JapanDepartment of Internal MedicineShinshu University School of Medicine, Matsumoto, Japan
| | - Katsuyoshi Masuda
- Institute for Molecular and Cellular RegulationGunma University, Maebashi 371-8512, JapanDepartment of General MedicineNational Defense Medical College, Tokorozawa, JapanSuntory Institute for Bioorganic ResearchOsaka, JapanDepartment of Internal MedicineShinshu University School of Medicine, Matsumoto, Japan
| | - Mitsuhisa Komatsu
- Institute for Molecular and Cellular RegulationGunma University, Maebashi 371-8512, JapanDepartment of General MedicineNational Defense Medical College, Tokorozawa, JapanSuntory Institute for Bioorganic ResearchOsaka, JapanDepartment of Internal MedicineShinshu University School of Medicine, Matsumoto, Japan
| | - Itaru Kojima
- Institute for Molecular and Cellular RegulationGunma University, Maebashi 371-8512, JapanDepartment of General MedicineNational Defense Medical College, Tokorozawa, JapanSuntory Institute for Bioorganic ResearchOsaka, JapanDepartment of Internal MedicineShinshu University School of Medicine, Matsumoto, Japan
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Kojima I, Nakagawa Y, Ohtsu Y, Hamano K, Medina J, Nagasawa M. Return of the glucoreceptor: Glucose activates the glucose-sensing receptor T1R3 and facilitates metabolism in pancreatic β-cells. J Diabetes Investig 2014; 6:256-63. [PMID: 25969708 PMCID: PMC4420555 DOI: 10.1111/jdi.12304] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/06/2014] [Revised: 10/16/2014] [Accepted: 10/21/2014] [Indexed: 01/29/2023] Open
Abstract
Subunits of the sweet taste receptor, namely T1R2 and T1R3, are expressed in mouse pancreatic islets. Quantitatively, the expression of messenger ribonucleic acid for T1R2 is much lower than that of T1R3, and immunoreactive T1R2 is in fact undetectable. Presumably, a homodimer of T1R3 could function as a signaling receptor. Activation of this receptor by adding an artificial sweetener, sucralose, leads to an increase in intracellular adenosine triphosphate ([ATP]c). This increase in [ATP]c is observed in the absence of ambient glucose. Sucralose also augments elevation of [ATP]c induced by methylsuccinate, a substrate for mitochondria. Consequently, activation of T1R3 promotes metabolism in mitochondria and increases [ATP]c. 3-O-Methylglucose, a non-metabolizable analog of glucose, also increases [ATP]c. Conversely, knockdown of T1R3 attenuates elevation of [ATP]c induced by glucose. Hence, glucose promotes its own metabolism by activating T1R3 and augmenting ATP production. Collectively, a homodimer of T1R3 functions as a cell surface glucose-sensing receptor and participates in the action of glucose on insulin secretion. The glucose-sensing receptor T1R3 might be the putative glucoreceptor proposed decades ago by Niki et al. The glucose-sensing receptor is involved in the action of glucose and modulates glucose metabolism in pancreatic β-cells.
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Affiliation(s)
- Itaru Kojima
- Institute for Molecular & Cellular Regulation, Gunma University Maebashi, Japan
| | - Yuko Nakagawa
- Institute for Molecular & Cellular Regulation, Gunma University Maebashi, Japan
| | - Yoshiaki Ohtsu
- Institute for Molecular & Cellular Regulation, Gunma University Maebashi, Japan
| | - Kunihisa Hamano
- Institute for Molecular & Cellular Regulation, Gunma University Maebashi, Japan
| | - Johan Medina
- Institute for Molecular & Cellular Regulation, Gunma University Maebashi, Japan
| | - Masahiro Nagasawa
- Institute for Molecular & Cellular Regulation, Gunma University Maebashi, Japan
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