Caloric restriction is associated with increased longevity and cancer resistance in many species. Recent work on mice with selective loss of insulin signaling—only in adipose tissue—suggested that reduced adiposity, not food restriction, extended longevity (Science 2003;299:572). To determine if this finding also applied to cancer prevention, three groups of SENCAR mice were treated with TPA following 10 weeks pretreatment: (a) ad libitum fed, sedentary; (b) exercise with pair feeding at the same amount as group a; and (c) 20% calorie restriction. Body weight and percent fat were significantly decreased in groups b and c after 10 weeks. Dorsal skin was shaved and topically treated with 3.2 nmol TPA, and tissue was harvested at necropsy 2 hours later. Subcutaneous fat in skin sections was evaluated by immunohistochemistry for two pathways of insulin/insulin growth factor (IGF-1)-dependent cellular signaling, PI3K and H-ras. Tissue was graded for staining density using computer standards under guidance of a pathologist without knowledge of tissue treatment. H-ras staining in TPA-treated subcutaneous fat was significantly different between groups: sedentary (a) vs exercise (b) was significant (p = .02) and sedentary (a) vs dietary restriction (c) was highly significant (p < .001). There were no significant differences in staining of PI3K in subcutaneous fat in any group. We conclude that the subcutaneous fat in SENCAR mice treated with TPA shows important decreases in the upstream IGF- MAPK pathway with either exercise or calorie restriction, not seen with downstream PI3K.
Supported by NIH R01CA106397, W.W.