Molecular Insights into the Adaptability of the Gut

Abstract

The small intestine delivers dietary fat in the form of triglyceride (TG)-rich lipoproteins to fuel the body. The production and clearance of TG-rich lipoproteins become dysregulated in people living with type 2 diabetes resulting in more dietary fat in circulation than healthy individuals following the same meal, contributing to cardiovascular risk. The response of the intestine to obesity through adaptive or maladaptive changes is not well understood. This thesis characterizes the intestinal response to diet-induced obesity and dyslipidemia, as well as extreme models of physiology including the ketogenic diet and chronic cold stress. I hypothesized that hormonal signalling regulates absorptive surface area which in turn modulates intestinal lipid metabolism in response to increases in energy intake. The second chapter evaluates the intestinal changes to chronic high-fat, high-cholesterol (HFHC) diet feeding in Ldlr⁻ᐟ⁻ mice with or without the addition of dietary nobiletin, a flavonoid previously shown to improve insulin sensitivity and attenuate atherosclerosis progression. Adding nobiletin to a HFHC diet normalized jejunal lipid storage and jejunal de novo synthesis of intestinal lipids. Lower fasting and post-prandial intestinal lipid levels achieved by nobiletin were associated with a more efficient handling of an acute dietary fat challenge, namely, greater intestinal TG secretion and clearance rates compared to mice fed the HFHC diet alone. The third chapter demonstrates that short-term ketogenic, but not HFHC diet feeding increases fasting intestinal lipid stores and intestinal surface area compared to controls. In response to an acute dietary fat challenge, mice previously fed the ketogenic diet had elevated plasma TG levels. The fourth chapter evaluates the requirement of glucagon-like peptide 1 receptor (GLP-1R), GLP-2R, and glucose-dependent insulinotropic polypeptide (GIPR) signalling in the expansion of intestinal surface area that occurs in response to the increased food intake that accompanies chronic cold stress in mice. Using Glp1r⁻ᐟ⁻Gipr⁻ᐟ⁻ and Glp1r⁻ᐟ⁻Glp2r⁻ᐟ⁻ mice, we found that cold stress-induced increases in jejunal villi length and crypt depth, but not small intestinal length, require GLP-2R signalling. Acute dietary fat challenges revealed no impact of cold stress on lipid handling in male mice, but in female mice, greater intestinal-TG secretion was observed in a GLP-1R/2R-dependent manner. Overall, these studies provide molecular insights into early and chronic changes in the intestinal response to increases in dietary fat or food intake. Furthermore, this thesis expands the intestinotrophic actions of endogenous gut hormone action and highlights sex differences in the intestinal response to these metabolic challenges.