In this study, we decomposed the total causal effects of obesity on the risk of CRC into three path-specific components: (1) direct effects, which are possibly mediated by unmeasured or currently unknown factors; (2) indirect effects that are mediated by circulating leptin and adiponectin; and (3) indirect effects that are not mediated by circulating leptin and adiponectin, but by hyperinsulinemia and chronic inflammation, represented by circulating C-peptide and CRP, respectively. The gene discussed is LEP; the disease is obesity due to melanocortin 4 receptor deficiency.