Leptin is elevated in
obesity and has been suggested to increase the risk of
colorectal cancer (CRC), although the evidence is conflicting. The objective of this study was to compare the susceptibility to colon
carcinogenesis of db/db mice that have highly elevated circulating
leptin and
leptin-deficient ob/ob mice, both of which are obese. Seven-week-old male ob/ob, db/db, and WT mice received 4 weekly i.p.
injections of 5 mg/kg
azoxymethane (AOM) and were killed 14 wk later for the analysis of putative preneoplastic
aberrant crypt foci (ACF). There were no differences in ACF number or multiplicity between ob/ob and db/db mice.
Leptin has been shown to induce
CYP2E1, the main
enzyme that activates AOM, but we observed no differences in hepatic
CYP2E1 activity or colonic
CYP2E1 protein levels between ob/ob and db/db mice. We also induced ACF with 2 oral doses 3 d apart of 30 mg/kg
methylnitrosourea (MNU), a direct-acting
carcinogen. There were no differences in ACF number or multiplicity between the two groups of obese animals 5 wk following the last dose of MNU. The colonic mucosa of db/db mice expressed significantly lower
mRNA levels of ObRa, the predominant short form of the
leptin receptor, compared to ob/ob mice, and following i.p. injection with 1 mg/kg recombinant mouse
leptin, exhibited significantly reduced p44/42 pMAPK compared to saline-treated controls. These results show that ObRa is functionally active in the colons of db/db mice. We conclude that
leptin does not play a significant role in ACF development.