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Obesity, particularly visceral adiposity, is an established risk factor for colorectal cancer (CRC) and this is thought to result, at least in part, from insulin resistance and chronic hyperinsulinemia that may be mediated by adipokines. Serum levels of adiponectin, the most abundant protein secreted from adipocytes, are decreased in obesity and are inversely associated with insulin resistance and hyperinsulinemia. The objective of this study was to determine whether elevated circulating adiponectin plays a role in colon carcinogenesis using adiponectin transgenic (AdTg) mice that have 2-3-fold elevated circulating adiponectin but similar body weights as wildtype (WT) littermates used as controls. Eight-week old male and female AdTg and WT mice were treated with 4 weekly injections of the colon-specific carcinogen azoxymethane (AOM). One week following the last dose of AOM, all mice were placed on a high-fat diet and killed 24 weeks later, at 36 weeks of age, for the analysis of colon tumors. Glucose tolerance tests (GTT) were performed by injecting 2g/kg dextrose or 1.25-1.5 g/kg dextrose into all 12-week and 32-35-week-old mice respectively, and measuring blood from the tail vein 15, 30, 60 and 120 min following glucose administration. There were no significant differences in colon tumor incidence, number or size between AdTg and WT mice of either sex. AdTg mice of both sexes displayed resistance to diet-induced decreases in insulin sensitivity. Our results show that constitutively elevated levels of circulating adiponectin in AdTg mice do not confer protection against the development of colon tumors., ((c) 2008 Wiley-Liss, Inc.)

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.

Circulating insulin-like growth factor I (IGF-I) is associated with increased risk of colorectal cancer. It is not clear, however, whether IGF-1 plays a direct causative role in colon carcinogenesis or whether it mediates the known promoting effects of insulin. The objective of this study was to determine the role of IGF-1 in colon carcinogenesis using liver-specific IGF-I deficient (LID) mice that exhibit 70% reductions in circulating IGF-I. Female and male LID mice were treated with the colon-specific carcinogen azoxymethane to induce aberrant crypt foci (ACF) or colon tumors. Female LID mice developed significantly fewer ACF and had normal insulin levels compared to controls. Male LID mice, however, were hyperinsulinemic and exhibited no significant differences in ACF development compared to controls. In the tumor study, both male and female LID mice were hyperinsulinemic and had no significant differences in tumor incidence or multiplicity compared to their respective controls. There was a significant 25% reduction in tumor size, however, in both male and female LID mice compared to controls. These data suggest that IGF-I deficiency attenuates the promoting effect of insulin on colon carcinogenesis and that IGF-I is an independent promoter of the growth of established tumors. Our findings implicate both IGF-I and insulin as important promoters of colon cancer development., (Copyright 2007 Wiley-Liss, Inc.)