Lasting effects of low-calorie sweeteners on glucose regulation, sugar intake, and memory

Low-calorie sweetener (LCS) consumption in children has increased due to widespread LCS presence in the food environment and efforts to mitigate obesity through sugar replacement. However, mechanistic studies on the impact of early-life LCS consumption are lacking. Therefore, we developed a rodent model to evaluate the effects of daily LCS consumption (acesulfame potassium, saccharin, or stevia) during adolescence on adult metabolic, gut microbiome, neural, and behavioral outcomes. Results reveal that habitual early-life LCS consumption disrupts post-oral glucose tolerance and impairs hippocampal-dependent memory in the absence of weight gain. Furthermore, LCS consumption reduces lingual sweet taste receptor expression and alters sugar-motivated appetitive and consummatory responses. RNA sequencing analyses reveal that LCS also impacts collagen- and synaptic signaling-related gene pathways in the hippocampus and nucleus accumbens, respectively, in a sex-dependent manner. Collectively, these results suggest that regular early-life LCS consumption yields long-lasting impairments in metabolism, sugar-motivated behavior, and hippocampal-dependent memory.

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3-Deoxyglucosone Induces Glucagon-Like Peptide-1 Secretion from STC-1 Cells via Upregulating Sweet Taste Receptor Expression under Basal Conditions

International Journal of Endocrinology ◽

10.1155/2019/4959646 ◽

2019 ◽

Vol 2019 ◽

pp. 1-10

Author(s):

Xiudao Song ◽

Fei Wang ◽

Heng Xu ◽

Guoqiang Liang ◽

Liang Zhou ◽

...

Keyword(s):

Signaling Pathway ◽

Transient Receptor Potential ◽

Taste Receptor ◽

Sweet Taste ◽

Receptor Expression ◽

Oral Glucose ◽

Intragastric Administration ◽

Sweet Taste Receptor ◽

Glucagon Like Peptide ◽

Glucagon Like Peptide 1

3-Deoxyglucosone (3DG) is derived from D-glucose during food processing and storage and under physiological conditions. We reported that glucagon-like peptide-1 (GLP-1) secretion in response to an oral glucose load in vivo and high-glucose stimulation in vitro was decreased by acute 3DG administration. In this study, we determined the acute effect of 3DG on GLP-1 secretion under basal conditions and investigated the possible mechanisms. Normal fasting rats were given a single acute intragastric administration of 50 mg/kg 3DG. Plasma basal GLP-1 levels and duodenum 3DG content and sweet taste receptor expression were measured. STC-1 cells were acutely exposed to 3DG (80, 300, and 1000 ng/ml) for 1 h under basal conditions (5.6 mM glucose), and GLP-1 secretion, intracellular concentrations of cyclic adenosine monophosphate (cAMP) and Ca2+, and molecular expression of STR signaling pathway were measured. Under the fasted state, plasma GLP-1 levels, duodenum 3DG content, and duodenum STR expression were elevated in 3DG-treated rats. GLP-1 secretion was increased in 3DG-treated cells under either 5.6 mM glucose or glucose-free conditions. 3DG-induced acute GLP-1 secretion from STC-1 cells under 5.6 mM glucose was inhibited in the presence of the STR inhibitor lactisole, which was consistent with the observation under glucose-free conditions. Moreover, acute exposure to 3DG increased the protein expression of TAS1R2 and TAS1R3 under either 5.6 mM glucose or glucose-free conditions, with affecting other components of STR signaling pathway, including the upregulation of transient receptor potential channel type M5 TRPM5 and the increment of intracellular Ca2+ concentration. In summary, the glucose-free condition was used to first demonstrate the involvement of STR in 3DG-induced acute GLP-1 secretion. These results first showed that acute 3DG administration induces basal GLP-1 secretion in part through upregulation of STR expression.

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Transformation of postingestive glucose responses after deletion of sweet taste receptor subunits or gastric bypass surgery

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00163.2012 ◽

2012 ◽

Vol 303 (4) ◽

pp. E464-E474 ◽

Cited By ~ 49

Author(s):

Maartje C. P. Geraedts ◽

Tatsuyuki Takahashi ◽

Stephan Vigues ◽

Michele L. Markwardt ◽

Andongfac Nkobena ◽

...

Keyword(s):

Gastric Bypass ◽

Glycemic Control ◽

Large Intestine ◽

Molecular Mechanisms ◽

Hormone Secretion ◽

Taste Receptor ◽

Sweet Taste ◽

Oral Glucose ◽

Isolated Pancreatic Islets ◽

Sweet Taste Receptor

The glucose-dependent secretion of the insulinotropic hormone glucagon-like peptide-1 (GLP-1) is a critical step in the regulation of glucose homeostasis. Two molecular mechanisms have separately been suggested as the primary mediator of intestinal glucose-stimulated GLP-1 secretion (GSGS): one is a metabotropic mechanism requiring the sweet taste receptor type 2 (T1R2) + type 3 (T1R3) while the second is a metabolic mechanism requiring ATP-sensitive K+(KATP) channels. By quantifying sugar-stimulated hormone secretion in receptor knockout mice and in rats receiving Roux-en-Y gastric bypass (RYGB), we found that both of these mechanisms contribute to GSGS; however, the mechanisms exhibit different selectivity, regulation, and localization. T1R3−/−mice showed impaired glucose and insulin homeostasis during an oral glucose challenge as well as slowed insulin granule exocytosis from isolated pancreatic islets. Glucose, fructose, and sucralose evoked GLP-1 secretion from T1R3+/+, but not T1R3−/−, ileum explants; this secretion was not mimicked by the KATPchannel blocker glibenclamide. T1R2−/−mice showed normal glycemic control and partial small intestine GSGS, suggesting that T1R3 can mediate GSGS without T1R2. Robust GSGS that was KATPchannel-dependent and glucose-specific emerged in the large intestine of T1R3−/−mice and RYGB rats in association with elevated fecal carbohydrate throughout the distal gut. Our results demonstrate that the small and large intestines utilize distinct mechanisms for GSGS and suggest novel large intestine targets that could mimic the improved glycemic control seen after RYGB.

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Faculty Opinions recommendation of Disordered control of intestinal sweet taste receptor expression and glucose absorption in type 2 diabetes.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.718020724.793479145 ◽

2013 ◽

Author(s):

Richard J Naftalin

Keyword(s):

Type 2 Diabetes ◽

Taste Receptor ◽

Sweet Taste ◽

Glucose Absorption ◽

Receptor Expression ◽

Sweet Taste Receptor

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Incretin release from gut is acutely enhanced by sugar but not by sweeteners in vivo

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.90636.2008 ◽

2009 ◽

Vol 296 (3) ◽

pp. E473-E479 ◽

Cited By ~ 127

Author(s):

Yukihiro Fujita ◽

Rhonda D. Wideman ◽

Madeleine Speck ◽

Ali Asadi ◽

David S. King ◽

...

Keyword(s):

Blood Glucose ◽

Sweet Taste ◽

Tolerance Test ◽

Oral Glucose ◽

Dependent Manner ◽

Glucose Levels ◽

Zucker Diabetic Fatty Rats ◽

Glucagon Like Peptide 1

Glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) are released during meals from endocrine cells located in the gut mucosa and stimulate insulin secretion from pancreatic β-cells in a glucose-dependent manner. Although the gut epithelium senses luminal sugars, the mechanism of sugar sensing and its downstream events coupled to the release of the incretin hormones are not clearly elucidated. Recently, it was reported that sucralose, a sweetener that activates the sweet receptors of taste buds, triggers incretin release from a murine enteroendocrine cell line in vitro. We confirmed that immunoreactivity of α-gustducin, a key G-coupled protein involved in taste sensing, is sometimes colocalized with GIP in rat duodenum. We investigated whether secretion of incretins in response to carbohydrates is mediated via taste receptors by feeding rats the sweet-tasting compounds saccharin, acesulfame potassium, d-tryptophan, sucralose, or stevia. Oral gavage of these sweeteners did not reduce the blood glucose excursion to a subsequent intraperitoneal glucose tolerance test. Neither oral sucralose nor oral stevia reduced blood glucose levels in Zucker diabetic fatty rats. Finally, whereas oral glucose increased plasma GIP levels ∼4-fold and GLP-1 levels ∼2.5-fold postadministration, none of the sweeteners tested significantly increased levels of these incretins. Collectively, our findings do not support the concept that release of incretins from enteroendocrine cells is triggered by carbohydrates via a pathway identical to the sensation of “sweet taste” in the tongue.

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Sweet taste receptor expression in ruminant intestine and its activation by artificial sweeteners to regulate glucose absorption

Journal of Dairy Science ◽

10.3168/jds.2014-8004 ◽

2014 ◽

Vol 97 (8) ◽

pp. 4955-4972 ◽

Cited By ~ 47

Author(s):

A.W. Moran ◽

M. Al-Rammahi ◽

C. Zhang ◽

D. Bravo ◽

S. Calsamiglia ◽

...

Keyword(s):

Taste Receptor ◽

Sweet Taste ◽

Glucose Absorption ◽

Receptor Expression ◽

Artificial Sweeteners ◽

Sweet Taste Receptor

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Sweet Taste Is Complex: Signaling Cascades and Circuits Involved in Sweet Sensation

Frontiers in Human Neuroscience ◽

10.3389/fnhum.2021.667709 ◽

2021 ◽

Vol 15 ◽

Author(s):

Elena von Molitor ◽

Katja Riedel ◽

Michael Krohn ◽

Mathias Hafner ◽

Rüdiger Rudolf ◽

...

Keyword(s):

Alternative Pathway ◽

Taste Receptor ◽

Physiological Role ◽

Primary Source ◽

Sweet Taste ◽

Receptor Expression ◽

Taste Bud ◽

Sweet Taste Receptor ◽

The Brain ◽

Taste Bud Cells

Sweetness is the preferred taste of humans and many animals, likely because sugars are a primary source of energy. In many mammals, sweet compounds are sensed in the tongue by the gustatory organ, the taste buds. Here, a group of taste bud cells expresses a canonical sweet taste receptor, whose activation induces Ca2+ rise, cell depolarization and ATP release to communicate with afferent gustatory nerves. The discovery of the sweet taste receptor, 20 years ago, was a milestone in the understanding of sweet signal transduction and is described here from a historical perspective. Our review briefly summarizes the major findings of the canonical sweet taste pathway, and then focuses on molecular details, about the related downstream signaling, that are still elusive or have been neglected. In this context, we discuss evidence supporting the existence of an alternative pathway, independent of the sweet taste receptor, to sense sugars and its proposed role in glucose homeostasis. Further, given that sweet taste receptor expression has been reported in many other organs, the physiological role of these extraoral receptors is addressed. Finally, and along these lines, we expand on the multiple direct and indirect effects of sugars on the brain. In summary, the review tries to stimulate a comprehensive understanding of how sweet compounds signal to the brain upon taste bud cells activation, and how this gustatory process is integrated with gastro-intestinal sugar sensing to create a hedonic and metabolic representation of sugars, which finally drives our behavior. Understanding of this is indeed a crucial step in developing new strategies to prevent obesity and associated diseases.

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Receptor Regulation in Taste: Can Diet Influence How We Perceive Foods?

J ◽

10.3390/j1010011 ◽

2018 ◽

Vol 1 (1) ◽

pp. 106-115 ◽

Cited By ~ 2

Author(s):

Ashkan Shahbandi ◽

Ezen Choo ◽

Robin Dando

Keyword(s):

Chronic Exposure ◽

Taste Receptor ◽

Receptor Expression ◽

Receptor Regulation ◽

Taste Receptors ◽

Receptor Sensitivity ◽

Small Pilot Study ◽

Monosodium Salt ◽

The Impact

Taste buds are the dedicated sensory end organs of taste, comprising a complex and evolving profile of signaling elements. The sensation and ultimate perception of taste depends on the expression of a diverse array of receptors and channels that sense their respective tastes. Receptor regulation is a recognized and well-studied phenomenon in many systems, observed in opioid addiction, insulin resistance and caffeine tolerance. Results from human sensory studies suggest that receptor sensitivity or expression level may decrease after chronic exposure to respective tastants through diet. We review data supporting the theory that taste receptors may become downregulated with exposure to a specific tastant, along with presenting data from a small pilot study, showing the impact of long-term tastant exposure on taste receptor expression in mice. Mice treated with monosodium salt monohydrate (MSG), saccharin and NaCl (typically appetitive tastes) all displayed a significant decrease in mRNA expression for respective umami, sweet and salty receptors/sensory channels. Reduced sensitivity to appetitive tastes may promote overconsumption of foods high in such stimuli.

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