Abstract
Background Metabolic syndrome is a complex disorder that increases the risk of cardiovascular diseases. Metabolic syndrome has an unknown aetiology, but shifting dietary patterns such as increased consumption of industry-processed refined sugars have been implicated in the pathogenesis of the syndrome. Distributed along the length of the alimentary tract are macronutrient sensing mechanisms that play a key role in regulating feeding behaviour and energy balance and control intestinal nutrient-transport capacity and the release of peptide hormones. Recent studies have suggested that the sweet-taste receptor, T1R2/3, senses small-intestinal glucose levels and co-ordinates transport capacity and GLP1 release; however, the precise role of T1R2/3 in intestinal sugar sensing remains controversial. Studies have also suggested that macronutrient sensing is attenuated in diet-related metabolic disease; however, the mechanisms by which this occurs are not known.Aims We hypothesised that T1R2/3 expressed in enterocytes regulates intestinal sugar-transport capacity. We also hypothesised that macronutrient sensors demonstrate a diurnal rhythm that is controlled by clock genes and that in obesity/diabetes the gene-expression levels of such sensors are diminished.
Methods To test our hypotheses we studied the expression levels of intestinal sugar sensors in nocturnal feeding rodents, rodents chronically fed a high-sucrose diet and Caco-2 cells — an enterocyte model.
Results T1R2/3 gene expression was highest in the tongue, absent from the stomach and detected at low levels in the small intestine. SGLT3, a novel sugar sensor, was not expressed in the tongue but was expressed in the stomach and small intestine. A clear diurnal rhythm of clock genes CRY2 and BMAL1 was found in the tongue, stomach and small intestine. A diurnal rhythm for T1R2, T1R3 and the novel sugar sensor SGLT3 was detected in the stomach and small intestine, but not the tongue. SGLT3 expression, but not T1R2/3, was significantly decreased in mice fed a high-sucrose diet. SGLT3 and T1R3, but not T1R2, were detected in Caco-2 cells; however, we found no evidence of a functional sweet-taste receptor.
Conclusion Taken together, these data suggest a novel interaction between intestinal clock genes and sugar-sensor mechanisms. Disturbances in clock gene/nutrient sensing interactions may be important in the development of diet-related diseases. T1R2/3 regulation of sugar transport most likely occurs via an enteroendocrine cell/enterocyte interaction.
| Date of Award | 2016 |
|---|---|
| Original language | English |
| Awarding Institution |
|
| Supervisor | Paul Sharp (Supervisor) & Christopher Corpe (Supervisor) |