The Role of the Insulin-like Growth Factor-1 Receptor in Intestinal Microvillus Structure and Lipid Handling, and its Requirement in Glucagon-like Peptide-2 Signaling and a Western Diet

Microvilli are the small structures that contain digestive enzymes and transporters, allowing the small intestine to carry out the digestion and absorption of dietary nutrients. Exogenous administration of degradation-resistant glucagon-like peptide-2 (GLP-2) has shown to enhance this function of the small intestine in several ways, two of which include increasing microvillus length as well as increasing enterocyte chylomicron synthesis and secretion. However, GLP-2 requires downstream mediators to elicit its effects. It is not known if the intestinal epithelial insulin-like growth factor-1 receptor (IE-IGF-1R) , a proven mediator for other known effects of GLP-2, is also required for the GLP-2-induced increases in microvillus length and enterocyte lipid handling. Furthermore, the role of the IE-IGF-1R itself within the gut is poorly understood. Therefore, this work sought to understand the role of IE-IGF-1R in microvillus length, both basally and under GLP-2 treatment conditions. In addition, the requirement of the receptor in lipid handling, both basally and during a Western diet were also investigated. Using intestinal epithelial-specific, inducible IE-IGF-1R knockout (KO) animals, it was found that GLP-2 increases microvillus length in an IE-IGF-1R-dependent manner, potentially through the up-regulation of villin. Furthermore, the receptor has an endogenous role in regulating microvillus length, as KO animals presented with shorter microvilli. The IE-IGF-1R was important in enterocyte lipid handling during a western diet, as these animals had increased plasma triglycerides, as well as elevated C14 labeled triolein levels in their plasma and jejunal mucosa. Furthermore, the KO animals did not have cluster of differentiation 36 (CD36) localized to the brush border, as well as failed to increase microsomal triglyceride transfer protein (MTP) and decrease apolipoprotein C3 (APOC3). Overall, it was found that the endogenous role of the IE-IGF-1R was important for microvillus length regulation. More importantly, it was found that the receptor was required for the GLP-2 -induced increase in microvillus length, as well as enterocyte lipid handling under a western diet. This work expands our knowledge of the receptor's role within the small intestine, as well as deepen our understanding of the mechanism of action of GLP-2.Ph.D