Effects of Omega-3 Fatty Acids on Insulin Resistance in an Ovariectomized Mouse Model of Diet-Induced Obesity Treated with Chemotherapy

Abstract

Abstract Objectives Our objective was to examine effects of dietary enrichment of eicosapentaenoic acid + docosahexaenoic acid (EPA + DHA) on high fat diet-induced insulin resistance during chemotherapy. Methods Adult, female C57Bl/6 mice (n = 48) were assigned to 1 of 3 diets; low-fat diet (LF; 10% kcals fat), high-fat diet (HF; 45% kcals fat), or HF diet with omega-3 s (HF n-3; 2% kcals EPA + DHA) for 7 weeks. Mice received vehicle or chemotherapy injections (doxorubicin + cyclophosphamide), by tail vein at week 4 and 6. Food intake and body weights were recorded. Fasted blood glucose and serum insulin were measured weekly. Homeostatic model assessment of insulin resistance (HOMA-IR) was calculated. Body composition was measured using Echo MRI. Data were analyzed using ANOVA; p < 0.05 was considered significant. Results Total kilocalories significantly differed by group (p < 0.001); HF and HF n-3 groups consumed more than the LF group (p < 0.001, p < 0.0001; respectively). Obesity was induced prior to first injection with body weights being significantly different (p < 0.01); the LF group weighed less than the HF n-3 group (p < 0.01), and there was a similar trend between LF and HF groups (p = 0.0519). Body weights at sacrifice significantly differed (p < 0.0001); chemotherapy mice weighed less than vehicle (p < 0.0001). Percent body fat at sacrifice significantly differed (p < 0.0001); chemotherapy mice had less fat than vehicle (p < 0.0001), and the LF group had less fat than HF (p < 0.01) and HF n-3 group (p < 0.01). Blood glucose significantly differed at sacrifice (p < 0.01); chemotherapy mice had lower glucose than vehicle (p < 0.05) and HF group had higher glucose than LF group (p < 0.01). HOMA-IR scores at sacrifice significantly differed (p < 0.05); chemotherapy mice had lower scores than vehicle (p < 0.05) and mice on the LF and HF n-3 diets had lower scores than the HF diet (p < 0.01; p < 0.05 respectively). Conclusions Chemotherapy lowered body weight and body fat in mice, potentially contributing to decreases in blood glucose and insulin resistance. EPA + DHA enrichment of a HF diet reduced insulin resistance in mice comparable to a LF diet group. This occurred in both chemotherapy and vehicle treated mice, despite LF diet-fed mice having lower body weight and adiposity. Underlying mechanisms are being investigated. Funding Sources NIH #5R01CA18994.