Electronic Thesis and Dissertation Repository


Doctor of Philosophy




Huff, Murray W.


Naringenin and nobiletin are naturally-derived citrus flavonoids that have significant lipid-lowering and insulin sensitizing effects in vitro and in vivo. In murine models of obesity, metabolic dysfunction and atherogenesis, these flavonoids protect against the development of cardiometabolic disease. However, the ability of naringenin and nobiletin to reverse existing metabolic dysfunction and atherosclerosis has not been investigated.

The purpose of this thesis was to investigate the ability of the citrus flavonoids, naringenin and nobiletin, to reverse obesity, metabolic syndrome and atherosclerosis in two different mouse models of atherosclerosis regression. The first chapter demonstrates in Ldlr-/- mice with diet-induced obesity, metabolic syndrome and atherosclerosis, that the addition of either naringenin or nobiletin to the high-fat diet completely reverses obesity and insulin resistance, and improves hyperlipidemia, hepatic steatosis and monocytosis. This leads to an improvement in lesion morphology, consistent with regression but no attenuation in plaque size. The second chapter built upon these studies by looking at the effects of naringenin in a more aggressive mouse model of atherosclerosis regression. Ldlr-/- mice with diet-induced metabolic dysfunction and atherosclerosis were intervened with chow diet supplemented with naringenin. Naringenin enhanced the reversal of obesity, hyperlipidemia, insulin resistance and monocytosis compared to intervention with chow alone. Lesions in the naringenin-treated mice were smaller, comprised of less macrophages and had more characteristics of increased lesion stability compared to lesions in mice intervened with chow alone. The third chapter further investigated the effects of naringenin in the absence of high-fat feeding. In lean, pair-fed Ldlr-/- mice, naringenin supplementation reduced adiposity, enhanced insulin sensitivity and lowered plasma lipids. Mechanistically, these metabolic improvements were due in part to enhanced energy expenditure and increased hepatic fatty acid oxidation, in the absence of obesity or high-fat feeding.

In summary, the studies in this thesis provide evidence and molecular insight into how treatment with citrus flavonoids can reverse metabolic dysfunction and contribute to the regression of atherosclerosis in a mouse model. Furthermore, this thesis highlights the therapeutic utility of naringenin and nobiletin, and further underscores their importance in future therapeutic development for metabolic syndrome and atherosclerosis.