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Ld lower than the cumulative doses needed to produce cancer in experimental animals [93-96], and beginning in early adolescence, we pair-fed the rats with either high (60 ) or low (5 ) fat containing diets. The NDEA doses were selected to be far below those needed for carcinogenesis and were based on empirical studies demonstrating absence of acute toxic effects in the rats.Longer durations of NDE
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Or NDEA-associated neurodegeneration and insulin/IGF resistance were likely mediated by increased brain ceramide levels. Those studies demonstrated strikingly increased expression of several genes regulating ceramide production via both de novo biosynthesis or sphingomyelin degradation pathways in NDEA-treated rats, irrespective of chronic HFD feeding. Since NDEA is lipid soluble [115,116] and can
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N exist inTable 2 High Fat Diet Feeding and NDEA Treatment Cause Type 2 Diabetes MellitusAssay Body Wt (g) Glucose (mg/dL) Insulin (ng/ml) Leptin Adiponectin Triglyceride (mg/ml) Free Fatty Acids (mM/mg prot) Cholesterol (mg/ml) LFD+VEH 265.100 ?14.050 111.5 ?1.66 0.0611 ?0.017 4.649 ?0.789 20864 ?1454 0.399 ?0.028 0.150 ?0.003 0.943 ?0.024 LFD+NDEA 266.600 ?19.970 128.8* ?4.31 0.163* ?0.038 4.775
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Of age. Biochem Mol Biol Int 1998, 44(1):1-7. 38. Haan MN: Therapy Insight: type 2 diabetes mellitus and the risk of lateonset Alzheimer's disease. Nat Clin Pract Neurol 2006, 2(3):159-166. 39. Reger MA, Watson GS, Green PS, Wilkinson CW, Baker LD, Cholerton B, Fishel MA, Plymate SR, Breitner JC, Degroodt W, Mehta P, Craft S: Intranasal insulin improves cognition and modulates beta-amyloid in earl
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Tylcholine receptor binding in the cerebellum and brainstem [103]. In previous studies using a mouse model of dietinduced obesity [45,46], we showed that chronic HFD feeding causes brain insulin resistance [46]. Similarly, herein we demonstrated that the HFD-fed rats had reduced levels of brain IRS-1 mRNA, which would have been sufficient to cause brain insulin resistance due to impaired transmiss
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E formation of DNA and protein adducts [105-107] that can serve as persistent sources of oxidative stress, and cause further DNA damage and protein dysfunction. Recently, we demonstrated a role for ceramidemediated neurodegeneration in a model of diet-induced obesity with T2DM [45], and showed that in vitro ceramide exposure causes neurodegeneration with impairments in neuronal viability, energy m
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R-group comparisons were made using ANOVA with the post-hoc Bonferroni multiple comparisons test of significance. Significant P-values are indicated within the panels.suggesting that early life exposures may contribute to the pathogenesis of AD, perhaps through gene imprinting. Although chronic HFD feeding and limited NDEA exposure increased body weight and caused T2DM/peripheral insulin resistanc
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S. Nutr Rev 2007, 65(12 Pt 2):S152-156. 2. Launer LJ: Next steps in Alzheimer's disease research: interaction between epidemiology and basic science. Curr Alzheimer Res 2007, 4(2):141-143. 3. Wang XP, Ding HL: Alzheimer's disease: epidemiology, genetics, and beyond. Neurosci Bull 2008, 24(2):105-109. 4. de la Monte SM, Neusner A, Chu J, Lawton M: Epidemilogical Trends Strongly Suggest Exposures as