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

Abstract

Obesity-induced inflammation is 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 alters CRC initiation and its relationship to altered hematopoiesis. Mice consumed either a control (CON) or a 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 euthanasia, body weight and fat mass were similar among all three groups ( P < 0.05). Compared with CON and HF-EX, HF-SED developed increased content of preneoplastic lesions ( P < 0.05), and HF-SED had significantly increased markers of colon inflammation compared with CON. Compared with 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 with CON and HF-EX ( P < 0.05), and proteomics analysis revealed an increased marker of bone marrow inflammation in HF-SED compared with CON and HF-EX. Our results suggest that the early removal of a high-fat diet reduces CRC incidence when combined with an exercise training intervention. This reduction in risk was related to lower colon inflammation with anti-inflammatory changes in hematopoiesis induced by exercise.

Endurance Exercise Mitigates Immunometabolic Adipose Tissue Disturbances in Cancer and Obesity

“…The authors concluded that exercise, in a dose-dependent manner, abolished the deleterious effects induced by obesity and also inferred that this positive outcome was modulated by the adipokine secretion (adiponectin and leptin) profile and adiponectin receptor 1 enhanced expression, that in turn, act on cell cycle inhibition [159]. Another study evaluated the cessation of a high fat diet, followed or not by exercise, on colon rectal cancer risk and the authors concluded that the positive effect of exercise was mediated by lowering inflammation to a similar level found on control animals that have never been obese before [160].…”

How Does Lifestyle Affect Hematopoiesis and the Bone Marrow Microenvironment?

“… 72 Even following subsequent weight loss, the chronic inflammatory state placed on the HSC niche leads to the accumulation of myeloid progenitors and LT- and ST-HSC depletion. 4 , 73 , 74 However, exercise mitigates these alterations in HSC activity. Circulating HSC concentrations have a noted increase following acute and endurance exercise training in mice.…”

“… 81 Furthermore, exercise training in previously obese mice who had undergone weight loss and were at increased risk of carcinogenesis restored the HSC frequency to levels in never obese mice. 4 Thus, the effects of exercise appear to be dependent on exercise dose and model in healthy conditions and to reduce aberrant HSC expansion in disease.…”

“… 9 , 83 Importantly, this increased hematopoietic activity in exercise-trained mice in the context of stress hematopoiesis does not appear to result in increased risk of hematological malignancies; however, the risk of hematological malignancies is increased in experimental models of obesity. 84 With respect to HSC fate decisions, exercise training induces a notable decrease in HSC myeloid-skewing under obesogenic conditions 4 and an increase in lymphopoiesis. 83 Collectively, these results suggest that, regardless of the effects of exercise training on HSC content, exercise training improves the functional capacity of HSCs to respond to hematopoietic stress and may restore HSC lineage commitment to reverse the inflammatory phenotype in obesity.…”

Common Sources of Inflammation and Their Impact on Hematopoietic Stem Cell Biology

“…Exercise attenuates the production of leptin in adipose tissue, which in turn enhances CXCL12, a quiescence-promoting hematopoietic niche factor important in the maintenance of HSC function [102••]. In a separate study, mice fed a high-fat diet without exercise showed increased common myeloid progenitor cells and BM inflammation [103]. Overall, these studies indicate that exercise maintains HSC function by decreasing inflammation within the BM niche.…”