Citrus flavonoid naringenin reduces mammary tumor cell viability, adipose mass, and adipose inflammation in obese ovariectomized mice.

SCOPE: Obesity-related metabolic dysregulation may be a link between obesity and postmenopausal breast cancer. Naringenin, a flavonoid abundant in grapefruits, displays beneficial effects on metabolic health and tumorigenesis. Here, we assessed the effects of naringenin on mammary tumor cell growth in vitro and in obese ovariectomized mice. METHODS AND RESULTS: Naringenin inhibited cell growth, increased phosphorylation of AMP-activated protein kinase (AMPK), down-regulated CyclinD1 expression, and induced cell death in E0771 mammary tumor cells. Obese ovariectomized mice were fed a high-fat (HF), high-fat diet with low naringenin (LN; 1% naringenin) or high-fat diet with high naringenin (HN; 3% naringenin) for 2 weeks and then implanted with E0771 cells in mammary adipose tissue. Three weeks after tumor cell implantation, naringenin accumulation in tumor was higher than that in mammary adipose tissue in HN mice. HN decreased body weight, adipose mass, adipocyte size, α-smooth muscle actin mRNA in mammary adipose tissue, and mRNA of inflammatory cytokines in both mammary and perigonadal adipose tissues. Compared with mice fed HF diet, HN delayed growth of tumors early but did not alter final tumor weight. CONCLUSION: Naringenin reduces adiposity and ameliorates adipose tissue inflammation, with a moderate inhibitory effect on tumor growth in obese ovariectomized mice.

The flavonoid, naringenin, decreases adipose tissue mass and attenuates ovariectomy-associated metabolic disturbances in mice.

OBJECTIVE: Adverse metabolic changes associated with loss of ovarian function increase the risk of developing metabolic syndrome and non-alcoholic fatty liver disease (NAFLD) in postmenopausal women. Naringenin improves metabolic disturbances in vitro and in vivo. In the present study, we tested the effects of naringenin on metabolic disturbances resulting from estrogen deficiency in ovariectomized mice. MATERIALS/METHODS: Ovariectomized C57BL/6 J female mice were fed a control diet (10% calories from fat) for 11 weeks. Mice either continued on the control diet (n = 9) or were switched to the control diet supplemented with 3% naringenin (n = 10) for the next 11 weeks. Energy expenditure was measured by indirect calorimetry and activity was monitored by infrared beam breaks. Intra-abdominal and subcutaneous adiposity was evaluated by magnetic resonance imaging (MRI). Blood biochemical measures of metabolic response included glucose, insulin, adipokines, and lipids. Lipid content in liver and muscle and expression of relevant genes in adipose tissue, liver, and muscle were quantified. RESULTS: Ovariectomized mice fed naringenin exhibited lower fasting glucose and insulin levels compared to controls, with over 50% reduction of intra-abdominal and subcutaneous adiposity. Plasma leptin and leptin mRNA in adipose depots were also decreased in mice fed a naringenin diet. Monocyte chemoattractant protein-1 (MCP1/Ccl2) and interleukin 6 (IL-6/Il6) mRNA expression levels were significantly lower in perigonadal adipose tissue of naringenin-supplemented mice. We also observed that mice fed a naringenin diet had less hepatic lipid accumulation with corresponding alterations of hepatic gene expression associated with de novo lipogenesis, fatty acid oxidation, and gluconeogenesis. CONCLUSION: Dietary naringenin attenuates many of the metabolic disturbances associated with ovariectomy in female mice.