Susceptibility to Induced and Spontaneous Carcinogenesis Is Increased in Fatless A-ZIP/F-1 but not in Obese ob/ob Mice

Abstract

Obesity is typically associated with increased tumor susceptibility, whereas caloric restriction, a regimen resulting in leanness, inhibits carcinogenesis. The link between adiposity and malignancies suggests that adipose tissue may influence carcinogenesis. An adipose tissue hormone, leptin, could be procarcinogenic because it stimulates proliferation in various tissues and tumor cell lines. Leptin may contribute to the correlation between adiposity and malignancies as its levels are usually increased in obese subjects and reduced by caloric restriction. We hypothesized that leptin deficiency, despite obesity, would inhibit carcinogenesis in leptin-null ob/ob mice and tested this hypothesis in two models: (a) two-stage skin carcinogenesis initiated by 7,12-dimethylbenz(a)anthracene and promoted by phorbol 12-myristate 13-acetate (PMA) and (b) p53 deficiency. Contrary to a typical association between obesity and enhanced carcinogenesis, obese ob/ob mice developed induced skin papillomas and spontaneous p53-deficient malignancies, mostly lymphomas, similarly to their lean littermates. Surprisingly, lipodystrophic (ZIP) mice that had very little both adipose tissue and leptin were highly susceptible to carcinogenesis. Hyperphagia, hyperinsulinemia, and hyperglycemia are unlikely to have contributed significantly to the enhancement of carcinogenesis in ZIP mice because similarly hyperphagic, hyperinsulinemic, and hyperglycemic ob/ob mice had normal susceptibility to carcinogenesis. Our data suggest that, in contrast to a well-known correlation between obesity and cancer, the direct effect of adipose tissue may rather be protective. (Cancer Res 2006; 66(17): 8897-902)

The Obesity-Cancer Link: Lessons Learned from a Fatless Mouse

“…Our recent studies using the A-Zip/F-1 mice (18) that have no white adipose tissue and undetectable leptin, adiponectin, and other adipokines showed that these mice are more susceptible to papilloma formation in a classic two-stage skin carcinogenesis experiment (19), a finding confirmed in a separate report (20). Furthermore, when A-Zip/F-1 mice were crossed to the C3(1)/Tantigen mammary tumor transgenic mouse model, they developed larger and earlier tumors (19).…”

Caloric restriction

“…This hypothesis has been tested in two separate models. First, by chemically inducing skin carcinogenesis using DMBA and then promoting it with phorbol 12-myristate 13-acetate (PMA) and second, by exploring the effects of leptin deficiency in mice also deficient in the tumor suppressor gene p53 (Ablamunits et al, 2006). Contrary to the expected association between obesity and enhanced carcinogenesis, obese ob/ob mice did not develop induced skin papillomas and spontaneous p53-deficient malignancies at a higher rate than their lean littermates -suggesting that indeed low leptin levels do provide some protection from cancer, which could partially explain the beneficial effect of CR.…”

“…Contrary to the expected association between obesity and enhanced carcinogenesis, obese ob/ob mice did not develop induced skin papillomas and spontaneous p53-deficient malignancies at a higher rate than their lean littermates -suggesting that indeed low leptin levels do provide some protection from cancer, which could partially explain the beneficial effect of CR. However, the effects of leptin are difficult to interpret because lipodystrophic (ZIP) mice that have both reduced leptin and low levels of adipose tissue were found to be highly susceptible to carcinogenesis (Ablamunits et al, 2006) indicating reduced leptin levels alone are unlikely to mediate the protective effect. Additionally, this role for leptin has been questioned (Brandon et al, 2009) by studies on the rate of melanoma tumor growth in lean and obese mice with leptin deficiency, or high levels of plasma leptin.…”

Mouse models of the metabolic syndrome

“…A-ZIP/F-1 mice develop liver steatosis, which accounts for the increased body weight. These mice are also hyperglycemic, hyperinsulinemic, hyperlipidemic and hypertensive (Moitra et al, 1998;Ablamunits et al, 2006;Lamounier-Zepter et al, 2008).…”