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Jia-Yu Ke Dissertation Final.pdf (10.66 MB)

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Bioactivity of Naringenin in Metabolic Dysregulation and Obesity-Associated Breast Cancer in a Mouse Model of Postmenopause

Ke, Jia-Yu
http://rave.ohiolink.edu/etdc/view?acc_num=osu1437479457

Abstract Details

2015, Doctor of Philosophy, Ohio State University, Nutrition Program, The Ohio State University.
Menopausal loss of ovarian function associates with changes in body composition, increasing the risk of developing central obesity, metabolic syndrome, and other chronic diseases. Breast cancer is the second leading cause of cancer deaths in women, with the majority occurring in postmenopausal women. Obesity is associated with increased risk of postmenopausal breast cancer and the underlying mechanism(s) likely involves obesity-related metabolic dysregulation. Therefore, improvement of metabolic status may be a useful approach to decrease the risk of breast cancer. Naringenin is a flavonone found in citrus fruits and tomatoes. It possesses anti-tumor properties as well as ameliorates obesity-associated metabolic dysregulation. Therefore, we hypothesized that naringenin ameliorates metabolic disturbances not only resulting from loss of ovarian function but also that associated with postmenopausal obesity. Furthermore, we hypothesized that naringenin inhibits mammary tumor growth induced by postmenopausal obesity. To determine the effect of naringenin on metabolic changes resulting from loss of ovarian function, ovariectomized C57BL/6J female mice were fed a control diet (10% kcal fat) for 11 weeks. Half of the mice were supplemented with 3% naringenin for the next 11 weeks. Ovariectomized mice exhibited hyperglycemia and increased adiposity. Naringenin supplementation decreased plasma leptin and leptin mRNA in adipose depots as well as adipose tissue inflammation. Naringenin-supplemented mice also had reduced hepatic lipid accumulation with corresponding alterations of hepatic gene expression associated with de novo lipogenesis and gluconeogenesis. Thus, dietary naringenin attenuated many of the metabolic disturbances associated with ovariectomy in female mice. Then, the effect of naringenin on metabolic disturbances in a mouse model of postmenopausal obesity was examined. Ovariectomized mice were fed a high-fat diet (60% kcal fat) for 11 weeks to induce obesity and half of the mice were then supplemented with 3% naringenin for another 11 weeks. Naringenin-fed mice had decreased weight gain, hyperglycemia, and intra-abdominal adiposity. Mice supplemented with naringenin also exhibited elevated locomotor activity, maintained muscle mass, reduced muscle diacylglycerol content and decreased muscle mRNA level for genes involved in de novo lipogenesis, lipolysis, and triglyceride synthesis/storage. Thus, naringenin supplementation attenuated metabolic dysregulation in obese ovariectomized mice. To determine the effect of naringenin on breast tumors growth in a mouse model of postmenopausal obesity, ovariectomized mice were fed a high-fat diet for 3 weeks to induce obesity and then supplemented with 1% or 3 % naringenin, or metformin, a glucose-lowering drug. After 2 weeks of experimental diets, E0771 murine breast cancer cells were inoculated into one mammary fat pad and the tumor size was monitored daily. Decreased body weight, adipose depot mass, and mRNA expression of inflammatory cytokines in both mammary and perigonadal adipose tissues were observed in naringenin-fed mice. Naringenin supplementation suppressed early tumor growth but not final tumor weight. Metformin reduced tumor growth and final weight, without affecting body weight, tissue weights, and adipose tissue inflammation. Collectively, our data demonstrated that naringenin and metformin alter mammary tumorigenesis via different mechanisms. Overall, these experiments suggest that naringenin supplementation may correct metabolic dysregulation induced by excess caloric consumption and/or loss of ovarian function.
Martha Belury (Advisor)
Earl Harrison (Committee Member)
Kichoon Lee (Committee Member)
Lisa Yee (Committee Member)
185 p.
Nutrition
flavonoids; naringenin; obesity; breast cancer; metabolic dysregulation; ovariectomy; postmenopause; menopause; metformin; bioactivity

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Citations

  • Ke, J.-Y. (2015). Bioactivity of Naringenin in Metabolic Dysregulation and Obesity-Associated Breast Cancer in a Mouse Model of Postmenopause [Doctoral dissertation, Ohio State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=osu1437479457

    APA Style (7th edition)

  • Ke, Jia-Yu. Bioactivity of Naringenin in Metabolic Dysregulation and Obesity-Associated Breast Cancer in a Mouse Model of Postmenopause . 2015. Ohio State University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=osu1437479457.

    MLA Style (8th edition)

  • Ke, Jia-Yu. "Bioactivity of Naringenin in Metabolic Dysregulation and Obesity-Associated Breast Cancer in a Mouse Model of Postmenopause ." Doctoral dissertation, Ohio State University, 2015. http://rave.ohiolink.edu/etdc/view?acc_num=osu1437479457

    Chicago Manual of Style (17th edition)

osu1437479457
804
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This open access ETD is published by The Ohio State University and OhioLINK.