This project has identified increased adiposity and altered plasma leptin levels to be not associated with colon sensitivity to a colon carcinogen using diet-induced obesity (DIO) rodent and defective leptin signalling mutant mouse models. These findings do not support a direct link between the deregulation of insulin and adipokine levels observed in obese rats with increased risk of colon carcinogenesis. However, elevated leptin levels associated with increased dietary fat intake did increase the risk of colon carcinogenesis, supporting previously reported studies. Increased adiposity was associated with altered plasma insulin, leptin and triglyceride levels and 69 mitochondrial associated proteins in DIO rats. The changes in these mitochondrial protein profiles were not correlated with changes at the gene expression level assessed using real-time PCR arrays. The rat colon mitoproteome analysis is also presented here to provide a useful tool in assisting identification and interpretation of mitochondrial dysfunction implicated in colon pathogenesis. Animal studies have shown altered leptin levels linked to obesity can disrupt normal processes in colon. The role of leptin receptors identified in the colon is unknown. Deregulation of IL6, IL1β and CXCL1 was associated with leptin signalling in colon tissue. Cross talk of leptin and insulin signalling by modulation of IGBP3, IGF2 and AKT1 were also highlighted. Leptin regulation of mitochondria-associated apoptotic pathways involving UCP2, CASP3 and CASP9 in the colon was also identified. The study presents novel strategies to dissect signalling cascades in colon influenced by obesity and links with colon cancer.