Mechanistic associations between
obesity and
colorectal cancer remain unclear. In this study, we investigated whether
adipokines are risk factors for
colorectal cancer and whether they may mediate its association with
obesity. In a case-cohort study nested within the Women's Health Initiative cohort of postmenopausal women, baseline plasma samples from 457
colorectal cancer cases and 841 subcohort subjects were assayed for seven
adipokines-
adiponectin,
leptin,
plasminogen activator inhibitor-1 (PAI-1),
resistin,
hepatocyte growth factor,
interleukin-6 (IL-6), and TNF-α. Serum
insulin and
estradiol values measured previously were also available for data analysis. After adjusting for age, race, smoking, colonoscopy history, and
estrogen level, a low level of anti-inflammatory
adiponectin and high levels of proinflammatory
leptin,
PAI-1, and
IL-6 were associated with increased
colorectal cancer risk, though only
leptin remained significant after further adjustment for
insulin [HRs comparing extreme quartiles (HR(Q4-Q1)), 1.84; 95% CI, 1.17-2.90]. Mediation analyses showed that
leptin and
insulin partially explained the association between waist circumference and
colorectal cancer and attenuated it by 25% and 37%, respectively, with
insulin being a significant mediator (P = 0.041). Our findings support the conclusion that
adipokines involved in
inflammation are associated with
colorectal cancer risk, but that their effects may be mediated mostly by
insulin, with
leptin exerting an independent effect.
Hyperinsulinemia and hyperleptinemia may therefore partially explain the adiposity association with
colorectal cancer in postmenopausal women.