Effects of obesity and exercise on colon cancer induction and hematopoiesis in mice.

Obesity-induced inflammation associated with increased risk for colorectal cancer (CRC). The role of diet and exercise in modulating increased CRC risk in obesity, and the potential role of altered hematopoiesis as a contributor to these effects remain unknown. The purpose of this study was to examine how weight loss induced during CRC induction with or without exercise alter CRC initiation and their relationship to altered hematopoiesis. Mice consumed either a control (CON) or high fat diet to induce obesity. All mice were then placed on the control diet during CRC induction with azoxymethane (AOM). Following AOM injection, mice originally on the high fat diet were randomized into sedentary (HF-SED) or exercise trained (HF-EX) conditions. At sacrifice, body weight and fat mass were similar amongst all three groups (p<0.05). Compared to CON and HF-EX, HF-SED developed increased content of pre-neoplastic lesions (P<0.05), and HF-SED had significantly increased markers of colon inflammation compared to CON. Compared to both CON and HF-EX, HF-SED had decreased content of short-term hematopoietic stem cells and increased content of common myeloid progenitor cells (both p<0.05). Similarly, HF-SED had increased bone marrow adiposity compared to CON and HF-EX (p<0.05), and proteomics analysis revealed increased marker of bone marrow inflammation in HF-SED compared to CON and HF-EX. Our results suggest that the early removal of high fat diet only reduces CRC incidence when combined with an exercise training intervention. This reduced in risk was related to lower colon inflammation with anti-inflammatory changes in hematopoiesis induced by exercise.