Nobiletin Corrects Intestinal Insulin Resistance and Lipid Metabolism in Ldlr-/- Mice Fed a High-fat Diet

The citrus flavonoid nobiletin has lipid lowering and insulin-sensitizing properties. In mice, nobiletin supplementation prevents high fat diet-induced dyslipidemia and insulin resistance. Interestingly, triglyceride mass remains elevated in the intestine of fasted high fat-fed mice, but not in nobiletin-supplemented mice. In this thesis, the mechanisms underlying the prevention of intestinal triglyceride retention by nobiletin were investigated. In male Ldlr-/- mice, nobiletin corrected intestinal insulin signaling resulting in normalization of de novo lipogenesis and decreased triglyceride for chylomicron synthesis and storage. In response to an oral fat load, nobiletin increased chylomicron-triglyceride secretion into plasma and enhanced plasma triglyceride clearance resulting in attenuated postprandial lipemia. Nobiletin also normalized gut hormone signaling and pancreatic β-cell mass to prevent hyperinsulinemia. Although nobiletin increased plasma GLP-2, GLP-2 antagonist administration did not inhibit nobiletin-induced chylomicron secretion. Finally, nobiletin protected high fat-fed female Ldlr-/- mice from dysregulated intestinal triglyceride metabolism but not from atherogenic cholesterol metabolism. These studies provide evidence for the therapeutic utility of nobiletin in improving intestinal insulin signalling and intestinal lipid metabolism