Abstract B3: Exercise and calorie restriction differentially regulate energy balance-related cell signaling pathways in a model of post-menopausal obesity

Abstract

Abstract B3 Epidemiological data suggest that induced negative energy balance through calorie restriction (CR) or increased exercise (EX) decreases postmenopausal breast cancer risk associated with obesity. Although the mechanism responsible for the beneficial effects of these anti-obesity strategies is not known, hormone alteration seems to play a critical role. Increased adiposity is associated with alterations in circulating adipokines, such as increased leptin and decreased adiponectin levels. In fact, reports show a positive correlation between leptin levels and breast cancer risk, and a negative association between adiponectin levels and breast-cancer patients. The aim of this study was to compare changes in adipokines and downstream signaling pathways proven to be altered in human breast cancers following either CR or EX in a mouse model of post-menopausal obesity. Ovariectomized female C57BL/6 mice (n=45) were administered a high-fat diet for 8 weeks to induce obesity. At week 9, these diet induced obesity (DIO) mice were randomized into 3 groups (n=15/group): control (AIN-76A diet ad libitum); CR (30% reduction in calories relative to control); EX (control diet + increased physical activity). The EX group was run on a variable speed treadmill for 45 minutes a day, five days a week at a maximum speed of 20 m/min At week 16, mice were euthanized and tissue was collected. At the end of the study, CR mice weighed significantly (p<.01) less than control mice (19.9 ± 0.5 vs. 28.8 ± 0.6 g, respectively) and the EX mice (26.0 ± 0.9). Although the CR mice weighed significantly less than the exercised mice, there was no difference in percent body fat between the groups (38.9 ± 1.7 vs. 33.7 ± 1.4 %, respectively), and both groups had significantly less percent body fat than the sedentary, ad libitum-fed controls (48.1 ± 1.9 %). CR, but not EX, demonstrated improved insulin sensitivity based on a glucose tolerance test compared to controls. Serum leptin levels were significantly reduced in CR and EX mice compared to controls and CR displayed increased serum adiponectin levels compared to exercise. Some of the cell signaling pathways regulated by these hormones, including AMPK, Akt and ERK, converge at mTOR; a molecule involved in coupling energy balance signals to protein translation and cell growth. Interestingly, mammary fat pads of CR, but not EX, displayed significantly higher AMPK phosphorylation and lower Akt phosphorylation relative to controls. Alternatively, mammary fat pads from both CR and EX displayed much lower levels of ERK phosphorylation compared to control. In addition, the key downstream effectors of mTOR activation such as S6 kinase and S6 ribosomal protein displayed decreased activation in both CR and EX compared to control. These data suggest that although EX can act on similar pathways as CR, CR possess a more global effect on cell signaling and therefore may produce a more potent anti-cancer effect. Citation Information: Cancer Prev Res 2008;1(7 Suppl):B3.