Mammary tumor growth limits spontaneous physical activity in high-fat diet fed mice housed in an enriched environment

Abstract

Aim:Excess weight and several pathological diseases such as cancer alter the total energy expenditureincluding both the resting and the activity energy expenditure. Moreover, the regular physical activity is considered as a protective factor in numerous physio-pathological situations. This study was designed to assess whether physical and social environment enrichment induces differential effects on tumor growth, and to determine their relation to metabolic consequences.Methods: 33-week-old C57BL/6 mice were randomly assigned to a high fat diet (HFD: 4.3 kcal/g, 45% of lipids, n=10/group/2 groups) or a standard diet (SD, 3.4 kcal/g, 10% lipids, n=10/group/2 groups). Among each diet group, mice were housed in an enriched environment (EE) or in standard laboratory environment (SE). After, 4 weeks of diet, the syngeneic EO771 spontaneous mammary adenocarcinoma cell line (5x105 cells) was orthotopically transplanted into the fourth right mammary gland. Tumor was allowed to growth during 1 month. Body weight, body composition (indirect calorimetry) and tumor growth were measured throughout the experiment. Mice spontaneous activity was evaluated by the PhenoMaster/LabMaster system (TSE System, Bad Homburg, Germany) connected to the calorimetric cages. Total spontaneous activity corresponded to the sum of vertical (z) and horizontal positions (xy). The distance covered by the mice were recorded during 1 week. Cages were or not equipped with a nest fixed in height or a running wheel to mimic respectively the EE and SE conditions. Data are presented as mean ± SD, statistical analysis were made using the Mann Whitney test.Results:In SE housing, individual horizontal movements were of 22 ± 8 m/h and vertical moving were 240 ± 60 passing/h In the EE conditions, horizontal movements decreased to 11 ± 5 m/h/mouse whereas vertical passages increased to 556 ± 83 passages/h/mouse (p<0,05). This effect was related to the presence of the nest in height favoring and limiting z and yz movements. Expressed in % of the ES conditions, the total spontaneous activity was enhanced by 40% (p<0.05). HFD comparatively to the SD was associated to a 39% reduction in the spontaneous locomotor activity (p<0.05) and to an increase in fat mass (30 vs 11%, p<0.01). After tumor implantation, HFD induced a higher tumor growth (1114 ± 793 vs 384 ± 339 mm3 at day 16, p<0.05) and a less spontaneous physical activity. In this condition, EE restricted both the tumor growth (663 ± 192 mm3 vs 1114 ± 793, p<0.05) and the loss in physical activity (p<0.05). However, tumor bearing reduced significantly the distance covered during the nocturnal period independently of the diets and the housing conditions. Whatever the diet and the housing condition, the tumor reduced the spontaneous locomotor activity of the diurnal period. So tumor development affects nocturnal/diurnal locomotor cycle.Conclusion: Both diet-induced-overweight and tumor reduce the mice spontaneous locomotor activity. In this context of metabolic perturbations, the enrichment of the housing allow to maintain a locomotor activity which is associated to a health benefit. This mouse model will allow to explore over time the metabolic and molecular mechanisms associated to the physical activity and its impact in the mammary carcinogenesi

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