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.