Title Page
Contents
Ⅰ. Introduction 9
Ⅱ. Literature review 14
1. Obesity and cognitive dysfunction 15
2. Molecular mechanism by which obesity induces cognitive dysfunction 18
3. Effect of ketogenic diet (KD) on body fat accumulation and obesity-related cognitive dysfunction 20
4. Effect of calorie restriction (CR) on body fat accumulation and obesity-related cognitive dysfunction 22
Ⅲ. Materials and methods 24
1. Animals and diets 25
2. Determination of blood ketone bodies 29
2.1. Blood beta-ketone concentration measurement 29
2.2. Beta-hydroxybutyrate (BHB) assay 29
3. Histological analysis of brain 30
4. Measurement of cognitive-behavioral function 30
4.1. Nest-building test 30
4.2. Y-maze test 31
5. Quantification of gene expression 33
6. Statistical analysis 35
Ⅳ. Results 36
1. Food intake, body weight, body fat mass, and brain weight 37
1.1. Food intake 37
1.2. Body weight 37
1.3. Body fat mass 37
1.4. Brain weight 38
2. Blood ketone bodies concentration 41
3. Histological change in brain 43
4. Cognitive function 48
5. Reactive oxygen species (ROS) synthesis in brain 54
6. Gene expression level of nuclear factor erythroid 2-related factor 2 (Nrf2) and glutathione peroxidase (Gpx) in brain 56
7. Pro-inflammatory cytokines gene expression level in brain 58
8. Apoptosis gene expression level in brain 60
Ⅴ. Discussion 62
Ⅵ. References 67
국문초록 77
Table 1. Diet composition 27
Table 2. Primer sequences 34
Table 3. Food intake, body weight, body fat mass, and brain weight 40
Figure 1. Research hypothesis. 13
Figure 2. Timeline of animal study. 28
Figure 3. Y-maze test. 32
Figure 4. Blood ketone bodies concentration. 42
Figure 5.1. Histological change in brain. 44
Figure 5.2. Histological change in dentate gyrus (DG). 45
Figure 5.3. Histological change in cornu ammonis 3 (CA3). 46
Figure 5.4. Histological change in cornu ammonis 1 (CA1). 47
Figure 6. Cognitive function in nest-building test. 51
Figure 7.1. Cognitive function in Y-maze test session 1. 52
Figure 7.2. Cognitive function in Y-maze test session 2. 53
Figure 8. NADPH oxidase 2 (Nox2) and NADPH oxidase 4 (Nox4) gene expression level in brain. 55
Figure 9. Gene expression level of nuclear factor erythroid 2-related factor 2 (Nrf2) and glutathione peroxidase (Gpx) in brain. 57
Figure 10. Pro-inflammatory cytokines gene expression level in brain. 59
Figure 11. Apoptosis gene expression level in brain 61