title: Dietary energy balance modulates signaling through the Akt/mammalian target of rapamycin pathways in multiple epithelial tissues.
abstract: The prevalence of obesity, an established risk factor for several types of cancer, has increased steadily over the past several decades in the United States. New targets and strategies for offsetting the effect of obesity on cancer risk are urgently needed. In the present study, we examined the effect of dietary energy balance manipulation on steady-state signaling in multiple epithelial tissues, with a focus on the Akt and mammalian target of rapamycin (mTOR) pathways. For these experiments, male FVB/N and C57BL/6 and female ICR mice were maintained on a control (10 kcal% fat) diet, a diet-induced obesity (DIO; 60 kcal% fat) regimen, or a 30% calorie restriction (CR) regimen for 15 to 17 weeks. Relative to the control group, the DIO regimen increased, whereas CR decreased, circulating insulin-like growth factor-I (IGF-I) as has previously been reported. Western blot analyses showed that the DIO regimen enhanced, whereas CR inhibited, activation of Akt and mTOR, regardless of epithelial tissue or genetic background. In contrast, activation of AMP-activated protein kinase was modulated by dietary energy balance manipulation in the liver but not in the epidermis or dorsolateral prostate. Western blot analyses of epidermal extracts taken from ICR mice also revealed reduced activation of both the IGF-I receptor and epidermal growth factor receptor in CR mice, compared with control mice or mice maintained on the DIO regimen. Taken together, these novel findings suggest that dietary energy balance modulates signaling through cell-surface receptors (i.e., IGF-I receptor and epidermal growth factor receptor), affecting activation of multiple downstream pathways including Akt and mTOR, thus providing important dietary and pharmacologic targets for disrupting the obesity-cancer link.
authors.affiliation: Science Park-Research Division, The University of Texas M. D. Anderson Cancer Center, Smithville, TX 78957, USA.
authors.forename: Tricia
authors.initials: T
authors.lastname: Moore
authors.forename: Linda
authors.initials: L
authors.lastname: Beltran
authors.forename: Steve
authors.initials: S
authors.lastname: Carbajal
authors.forename: Sara
authors.initials: S
authors.lastname: Strom
authors.forename: Jeanine
authors.initials: J
authors.lastname: Traag
authors.forename: Stephen D
authors.initials: SD
authors.lastname: Hursting
authors.forename: John
authors.initials: J
authors.lastname: DiGiovanni
mesh_terms: D000818:Animals; D050218:Body Fat Distribution; D001835:Body Weight; D004032:Diet; D004435:Eating / Q000502:physiology; D004734:Energy Metabolism / Q000502:physiology*; D004848:Epithelium / Q000378:metabolism*; D005260:Female; D006706:Homeostasis / Q000502:physiology; D007334:Insulin-Like Growth Factor I / Q000032:analysis / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008813:Mice, Inbred ICR; D051058:Oncogene Protein v-akt / Q000378:metabolism / Q000502:physiology*; D011494:Protein Kinases / Q000378:metabolism / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology; D058570:TOR Serine-Threonine Kinases
chemical_list: D007334:Insulin-Like Growth Factor I; D011494:Protein Kinases; C546843:mTOR protein, mouse; D051058:Oncogene Protein v-akt; D058570:TOR Serine-Threonine Kinases