Electronic Thesis and Dissertation Repository

Thesis Format

Integrated Article

Degree

Master of Science

Program

Biochemistry

Supervisor

Huff, Murray W.

Abstract

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.

Summary for Lay Audience

A natural compound isolated from tangerine peels called nobiletin has beneficial properties including improving the action of insulin. Insulin is a hormone secreted from the pancreas into the blood stream after a meal that helps cells of our body to use and store the energy (glucose) from our diet. Overconsumption of high-calorie foods causes an over-secretion of insulin and eventually, cells become resistant to insulin action. When we feed mice a high-fat diet, they develop insulin resistance, obesity, high levels of blood fats (such as cholesterol) and fat accumulates in fat cells as well as in other organs such as the liver. Previously, we have reported that in mice, adding nobiletin to a high-fat diet corrects insulin resistance, prevents obesity, lowers blood fats and prevents liver fat accumulation. Nobiletin works by increasing the burning of fats in the liver. The small intestine, which is responsible for absorbing and packaging dietary fat for delivery into the bloodstream, has been shown to contribute to dangerous blood fat levels. We asked the question – Does nobiletin also improve the way the small intestine handles fat? Intriguingly, when mice are fed a high-fat diet, but not a low-fat diet, the small intestine accumulates fat, even in the fasted state. The addition of nobiletin to the high-fat diet completely prevented this fasting fat accumulation. In this thesis, we studied how nobiletin prevents fasting intestinal fat accumulation. In male mice, nobiletin prevented insulin resistance in cells of the intestine resulting in the normalization of the amount of fat stored. In response to a fat meal, nobiletin increased the rate at which packaged fat exits the intestine and enters the blood stream. Once in the blood, the rate at which this blood fat was cleared from the circulation was much faster compared to mice fed the high fat diet alone. In the pancreas, nobiletin normalized insulin stimulation and decreased insulin storage to prevent high-blood insulin. We also investigated the protective effects of nobiletin, for the first time, in female mice. Nobiletin prevented obesity and fasting fat accumulation in the intestine. While some blood fats were normalized with nobiletin treatment, cholesterol levels were just as high as in the mice fed the high-fat diet alone. These studies provide new evidence for the contribution of the intestine to high blood-fat levels, they highlight the potential of nobiletin as a treatment and they demonstrate the importance of studying both sexes.

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