臺灣博碩士論文加值系統

Epidemiological and clinical studies suggest a mutual interaction between metabolic disorders and mood disorders. Obesity-associated metabolic dysregulations have a link to the pathogenesis of depression, a common form of mood disorders. Increased glutamatergic afferents from the ventral hippocampus to the nucleus accumbens, the brain reward centre, induce depressive phenomenon. To conserve the glutamate homeostasis, reuptake of glutamate via astrocytic glutamate transporters (GLAST and GLT-1) is essential. Previously, it has been demonstrated that chronic high-fat diet (HFD) feeding induces downregulations of GLAST and GLT1 in the ventral hippocampus and knockdown of GLAST and GLT1 induces depression-like behaviors in naïve mice. However, the regulatory mechanism of these two transporters in metabolic disorder-induced depression remains unclear. Here, I showed that 12-week HFD feeding induced not only metabolic disorders but also depression-like behaviors, i.e., low sucrose preference test score (anhedonia) and high forced swimming test score (despair). Furthermore, levels of GLAST and GLT1 in the ventral hippocampus were decreased in these HFD mice. Because HFD mice had increased levels of free fatty acids (FFAs) in their plasma I examined if FFAs affect the expression of GLAST and GLT1 using the rat cortical primary astrocytes. Initially, I found that HFD plasma decreased the expressions of GLAST and GLT1. Saturated fatty acids, stearic acids (C18), but not palmitic acid (C16) or octanoic acid (C8), downregulated the expressions of glutamate transporters. It has been demonstrated that the transcription factor Yin-Yang 1 (YY1) is negative, while nuclear factor kappa-B (NF-κB) is a positive regulator of GLAST and GLT-1. However, levels of YY1 in primary astrocytes were decreased after C18 treatment. Primary astrocytes treated with C18 had significantly reduced levels of phosphorylated NF-κB, while treated with betulinic acid, a triterpene known to inhibit NF-κB phosphorylation, reduced the expressions of GLAST and GLT-1. Furthermore, C18 reduced the levels of phosphorylated AKT, which is known to promote the activation of NF-κB. As AKT is one of the major intracellular messengers of the insulin-mediated pathways, the effect of C18 on insulin resistance was examined in the primary astrocytes. I found that insulin increased phosphorylation of AKT, NF-κB in primary astrocytes. Moreover, Insulin increased the expression level of glucose transporters 1 (GLUT1), an insulin-sensitive protein expressed in astrocytes as well GLAST and GLT-1 in primary astrocytes. The levels of insulin-induced AKT and NF-κB phosphorylation were inhibited by C18 pretreatment. Furthermore, C18 decreased the levels of GLUT1, indicating a reduced insulin sensitivity. Co-treatment of primary astrocytes with pioglitazone, a well-established insulin-sensitizing agent improved insulin sensitivity (increased phosphorylation of AKT and expression level of GLUT1) and upregulated the expression of GLAST and GLT-1 in C18 treated cells. In conclusion, metabolic disorder-related depression is associated with downregulations of astrocytic GLAST and GLT-1 in the ventral hippocampus, which can be caused by long-chain saturated fatty acid-induced insulin resistance.

Abstract I
Acknowledgement III
List of tables VIII
List of figures VIII
Abbreviations X
CHAPTER -1 1
1. Introduction 1
1.1 Obesity and metabolic disorders: periphery to CNS 1
1.2 Metabolic disorders and depression: 5
1.3 Astrocytic pathology, depression and glutamatergic transmission 6
1.4 Regulation of glutamate transporters (GLAST/GLT-1) 10
CHAPTER-2 14
2. Significance, Hypothesis and Specific Aims 14
CHAPTER-3 16
3. Materials and Methods 16
3.1 Animals 16
3.2 HFD feeding 16
3.3 Measurements of plasma glucose, insulin and FFAs levels 17
3.4 Sucrose preference test 17
3.5 Forced swimming test 18
3.6 Lentivirus preparation 18
3.7 Knock-down of the hippocampal expression of GLAST and GLT-1 in naive mice 19
3.8 Collection of plasma 20
3.9 Brain tissue preparation 20
3.10 Culture of Primary astrocytes 21
3.11 Preparation of BSA conjugated fatty acids (FAs) 22
3.12 Plasma treatment protocol 22
3.13 MTT Assay 23
3.14 Fatty acids treatment protocol 23
3.15 Betulinic acid treatment protocol 23
3.16 Insulin treatment protocol 24
3.17 Pioglitazone treatment protocol 24
3.18 Cell lysate and sample preparation 24
3.19 Immunoblotting 25
3.20 Statistical analysis 25
CHAPTER-4 27
4. Results 27
4.1 Twelve-week High fat diet (HFD) changes body weight and glucose metabolism. 27
4.2 Twelve-week HFD induces depression-like behavior 27
4.3 Twelve-week HFD reduces expression of GLAST and GLT-1 in ventral hippocampus but not in medial prefrontal cortex or amygdala 28
4.4 Hippocampal knock down of GLAST and GLT-1 induces depression-like behaviors in naïve mice 28
4.5 Twelve-week HFD plasma decreases the expression of GLAST and GLT1 in rat cortical primary astrocytes 29
4.6 Stearic acid (C18) but not palmitic acid (C16) or Octanoic acid (C8) reduced the expression level of GLAST and GLT-1 in primary astrocytes 29
4.7 C18 suppresses the phosphorylation of nuclear factor-κB (NF-κB) 30
4.8 Betulinic acid, a NF-κB inhibitor, decreases the expression level of GLAST and GLT1 in primary astrocytes. 31
4.9 C18 decreases the phosphorylation level of AKT in rat cortical primary astrocytes 32
4.10 C18 reduces insulin sensitivity (decreases the glucose transporters-1) in rat cortical primary astrocytes 32
4.11 Insulin increases the phosphorylation level of AKT, NF-κB and increased the expression level of GLUT1, GLAST and GLT-1 in rat cortical primary astrocytes in rat cortical primary astrocytes 33
4.12 C18 inhibits the insulin-induced AKT and NF-κB phosphorylation in primary astrocytes 34
4.13 Pioglitazone alleviates insulin resistance and increase the expression level of GLAST and GLT-1 in C18-treated primary astrocytes 34
CHAPTER-5 36
Discussion 36
CHAPTER-6 44
Conclusion 44
CHAPTER-7 45
References 45
CHAPTER-8 62
TABLES 62
CHAPTER-9 63
FIGURES 63

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