Central FoxO3a and FoxO6 Expression is Downregulated in Obesity Induced Diabetes but not in Aging

Background: Recent data suggest that insulin-like growth factor (IGF)-1 resistance in neurons prolongs longevity. In C. elegans this effect is mediated via DAF-16 the ortholog of the mammalian Fox() transcription factors. 3 different Fox transcription factors (FoxOs) are expressed in rodent CNS: FoxO1, FoxO3a and FoxO6. Methods: To define whether the different FoxOs are region-, sex- and age-specifically expressed, we analyzed Fox() mRNA levels in different brain regions from 6, 16,60 and 100 weeks old mice using realtime-PCR. In addition, we fed mice a high fat diet (HFD) to experimentally induce obesity and diabetes and analyzed Fox() mRNA in the different brain regions. Results: Interestingly, FoxO1 was predominantly expressed in the hippocampus whereas FoxO3a was quantitatively the most abundant Fox in the neocortex. During aging, FoxO1 expression peaked in all brain regions at 16 weeks and FoxO6 showed its highest expression at 60 weeks in the parietal and occipital cortex. In 6 weeks old mice FoxO6 expression was higher in male compared to female mice in the hippocampus and all cortical regions. Surprisingly, in HFD animals FoxO3a was significantly less expressed in the cerebellum and all cortical regions compared to control animals. Even more dramatic, FoxO6 expression dropped about 80% in all brain regions in response to HFD. Conclusion: Thus, FoxOs in the CNS showed a highly distinct expression, which in addition was age- and sex-dependent. In contrast to FoxO1, FoxO3a and FoxO6 were specifically diminished in the CNS of HFD animals possibly contributing to the reduced lifespan observed in these animals.