<p>As obesity has become one of the most prevalent metabolic
diseases, and diabetes
mellitus has become the seventh leading causes of death in the United States,
alternative food/nutrition-based approaches to tackle obesity that are both
efficacious and cost effective are in high demand. Since starch and its derived
products are the principal dietary supply of glucose, strategies of using
slowly digestible starch to achieve moderated glycemic response and prolonged
glucose delivery, as well as to locationally digest starch into the ileum, have
shown successful results such as moderation of insulinemia and reducing food intake
in obese animals. An important regulator of appetite suppression is the
neuroendocrine system of the gut-brain axis. Glucagon-like peptide-1 (GLP-1),
oxyntomodulin (OXM), and peptide YY (PYY) are the main anorexigenic peptide
products of the intestinal enterendocrine L-cells that regulate postprandial
insulin levels as well as satiety signals. The stimulation of the
enteroendocrine L-cells throughout the gastrointestinal tract through glucose,
fatty acids and proteins has been extensively studied and confirmed. However,
the stimulatory effect of complex dietary carbohydrates on L-cells is not
described. In this dissertation, we investigated the <i>in vitro</i> intestinal
cell chemosensation of L-cells to α-amylase starch digestion products, named
maltooligosaccharides (MOS), and in the possible application of using slowly
digestible starch delivery of MOS <i>in vivo</i>.</p>
<p>In Chapter II of this dissertation, we reported a
significantly higher stimulatory effect of MOS on GLP-1 and OXM secretion
compared to glucose in mouse and human L-cells, respectively. Additionally,
maltotriose enhanced the relative expression of the gastrointestinal peptide,
cholecystokinin. Moreover, MOS exhibited protective effects on barrier function
and monolayer integrity of intestinal epithelial cells. </p>
<p>In Chapters III and IV, we performed a multiomics approach
where transcriptomic analysis and global protein profiling of mouse L-cells
treated with different types of MOS showed that the carbohydrates exhibit their
effects through the induction of exocytosis of GLP-1- or OXM-containing
vesicles and not through a positive regulation of the proglucagon gene
expression. It is suggested that MOS induce higher secretion, but not higher
synthesis, of the proglucagon gene products. In addition, maltotriose treatment
downregulated the relative expression of the glucotoxicity marker,
thioredoxin-interacting protein, and upregulated the relative expression of
tight junction proteins supporting a role of MOS in barrier function integrity.</p>
<p>Translating the <i>in vitro</i> findings into an <i>in vivo</i>
application that is beneficial for human health required the use of
controllable tool for the delivery of MOS throughout the small intestine for
sensing by a higher number of L-cells. Slowly digestible starch (SDS), compared
to rapidly digestible starch, provided such a tool. For this purpose, we used
alginate-entrapped SDS microspheres that digest distally into the ileum to
examine the role of SDS in the intervention and prevention of obesity in
C57BL/6J diet-induced obese (DIO) and lean mice models.</p>
<p>Results showed that 20% SDS in low-fat diets significantly
improved weight loss and food intake reduction in DIO mice converted to low-fat
diet for 12 weeks. Similarly, 15% SDS in high-fat diets showed significant
reduction in body fat percent and significant increase in lean body mass as
well as considerable reduction in weight gain rate and food intake in lean mice
fed on 45% of calories high-fat diet. Immunohistochemistry of small intestine
of mice in both the intervention and prevention studies revealed an even and
thorough distribution of GLP-1 positive L-cells.</p>
<p>Overall, this dissertation proposes several insights into
L-cell sensation of dietary starch-degraded MOS delivered by the consumption of
slowly digestible starch. MOS exhibit unique influences on L-cell sensitivity
and gut hormone productivity. Future research investigating the mechanisms of
intestinal sensing of MOS, as well as the development of bioactive carbohydrate
structures that could preserve body weight and modulate glucose tolerance <i>in
vivo</i> is needed to translate these findings into nutritional recommendations
and food products beneficial for human health. The intricate role of dietary
carbohydrates on gut physiological response, related to satiety and food intake
could be a new approach for design of foods for health applications.</p>
| Identifer | oai:union.ndltd.org:purdue.edu/oai:figshare.com:article/7464944 |
| Date | 14 January 2021 |
| Creators | Marwa Mohamed Mohamed El Hindawy (5929655) |
| Source Sets | Purdue University |
| Detected Language | English |
| Type | Text, Thesis |
| Rights | CC BY 4.0 |
| Relation | https://figshare.com/articles/thesis/Maltooligosaccharide_Chemosensation_By_Intestinal_Enteroendocrine_L-Cells_Regulates_the_Endogenous_Release_of_Gut_Hormones_and_Contributes_to_Weight_Management_In_Vivo/7464944 |
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