Abstract 531: Sex Differences In The Metabolic Switch From Fasting To Refeeding In The Murine Jejunum

Abstract

Introduction: The small intestine receives hormonal and neuronal stimuli to ensure sufficient nutrient absorption to fuel the body. Insulin resistance promotes aberrant dietary fat delivery into circulation, increasing the risk of cardiovascular disease. The mechanisms underlying the loss of controlled dietary fat delivery during metabolic disease are unclear. We aimed to characterize the metabolic pathways engaged in the small intestine in the transition from fasting to refeeding states in both male and female mice. Methods: Eight- to twelve-week-old male and female mice fasted for 24 hours. Half of the mice were euthanized in the fasted state, and the remaining half were euthanized after a 4-hour refeeding period (Teklad Global 19% Protein Extruded Diet). Gene expression and pathway analyses in jejunal samples were determined using Nanostring. Results: In male and female mice, refeeding significantly upregulated pathways in amino acid synthesis, mitochondrial respiration, and proto-oncogene Myc signalling compared to fasting. Refeeding significantly downregulated glycolysis, and both mitogen-activated MAPK and PI3K signalling pathways compared to fasting. Interestingly, in males refeeding significantly upregulated AMPK, mTOR, and autophagy, whereas conversely in female mice, refeeding downregulated these pathways. Surprisingly, fatty acid synthesis and fatty acid oxidation pathways were unchanged by the nutritional state in males, but in females, both pathways were significantly downregulated with refeeding compared to fasting. In female mice, refeeding significantly reduced small intestinal length compared to fasting, whereas intestinal length was unchanged in male mice. Conclusions: Metabolic pathways well-characterized in the liver are often mechanistically extrapolated to the gut. We have begun to uncover the jejunal gene expression changes regulated by nutrient availability in male and female mice. Identifying how high-fat feeding dysregulates these pathways will help further elucidate the mechanism underlying the over-production of intestinally-derived lipoproteins in metabolic disease.