Impact of carbohydrate restriction in the context of obesity on prostate tumor growth in the Hi-Myc transgenic mouse model

INTRODUCTION: Previously, we showed that carbohydrate restriction with calorie restriction slowed tumor growth in xenograft mouse prostate cancer models. Herein, we examined the impact of carbohydrate restriction without calorie restriction on tumor development within the context of diet-induced obesity in the Hi-Myc transgenic mouse model of prostate cancer. METHODS: Mice were randomized at 5 weeks of age to ad libitum Western diet (WD; 40% fat, 42% carbohydrate; n=39) or ad libitum no carbohydrate ketogenic diet (NCKD; 82% fat, 1% carbohydrate; n=44). At age 3 or 6 months, mice were sacrificed, prostates weighed and prostate histology, proliferation, apoptosis, and macrophage infiltration evaluated by H&E, Ki67, TUNEL and F4/80 staining, respectively. Body composition was assessed by DEXA, serum cytokines measured using multiplex, and Akt/mTOR signaling assessed by Western. RESULTS: Caloric intake was higher in the NCKD group, resulting in elevated body weights at 6 months of age, relative to the WD group (45g vs. 38g; p=0.008). Despite elevated body weights, serum MCP-1 and IL-1α levels were lower in NCKD versus WD mice (p=0.046 and p=0.118, respectively), and macrophage infiltration was reduced in prostates of NCKD versus WD mice (p=0.028). Relative Akt phosphorylation and phospho-S6 ribosomal protein levels were reduced in prostates of NCKD versus WD mice. However, while mice randomized to NCKD had smaller prostates after adjustment for body weight at 3 and 6 months (p=0.004 and p=0.002, respectively), NCKD mice had higher rates of adenocarcinoma at 6 months compared to WD mice (100% vs. 80%, p=0.04). CONCLUSIONS: Despite higher caloric intake and elevated body weights, carbohydrate restriction lowered serum MCP-1 levels, reduced prostate macrophage infiltration, reduced prostate weight, but failed to slow adenocarcinoma development. Together, these data suggest that although carbohydrate restriction within the context of obesity may reduce obesity-associated systemic inflammation, it is not sufficient to counteract obesity-associated tumor growth.