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研究生：	許津如 Hsu, Chin-Ju
論文名稱：	探討飲食調整對於高脂飲食誘發情緒障礙老鼠的影響 Exploring the effects of dietary modification on high-fat-diet-induced mood disorder in mice
指導教授：	陳韻雯 Chen, Yun-Wen
學位類別：	碩士 Master
系所名稱：	醫學院 - 藥理學研究所 Department of Pharmacology
論文出版年：	2021
畢業學年度：	109
語文別：	英文
論文頁數：	53
中文關鍵詞：	飲食調節、肥胖、憂鬱症、谷氨酸天冬氨酸轉運蛋白、谷氨酸轉運蛋白 1
外文關鍵詞：	dietary modification, obesity, depression, glutamate aspartate transporter, glutamate transporter 1
相關次數：	點閱：169 下載：0
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很多研究都指出肥胖患者有更高的機率罹患憂鬱症，而目前治療肥胖的其中一個方式就是飲食調整。根據過往的文獻表明，高脂飲食會促使小鼠中海馬迴的星形膠質細胞的活化並且會改變星形膠質細胞的病理形態。此外，根據我們實驗室先前的研究指出，一個月的飲食調整可以改善高脂飲食所造成的肥胖小鼠的肥胖症狀。但是，飲食調整對降低高脂飲食所造成的類憂鬱行為和細胞間異常調節的作用仍然需要被深入了解。因此，該研究目的在研究代謝失調的改善是否可以緩解高脂飲食所造成的肥胖小鼠的類憂鬱行為。首先，我們餵養 8 周大的 C57BL / 6N 的小鼠高脂飼料時間長達三個月，以此來促使行成肥胖和類憂鬱行為。我們的實驗數據顯示，跟正常飲食的小鼠相比，餵食高脂飼料的小鼠的體重顯著增加。高脂飲食確實在小鼠中誘發了類憂鬱行為。接著我們用正常飲食餵養肥胖小鼠，藉以實行長達一個月飲食調整。經過一個月的飲食調整，肥胖小鼠的體重減輕，類憂鬱行為得以逆轉。然而，通過蛋白質印跡法，飲食調整對小鼠腹側海馬迴中的高脂飲食所導致表現量上升的膠質原纖維酸性蛋白(GFAP)表達沒有影響。接下來，我們在小鼠腹側海馬中進行了 GFAP 的免疫組化。通過分析星形膠質細胞的精細結構，我們發現飲食調節將改善高脂飲食所造成的小鼠腹側海馬迴 CA1 和 CA3 區星形膠質細胞縮短的總過程長度，並且減少星形膠質細胞分支點的數量。在高脂飲食所造成的肥胖小鼠中，與星形膠質細胞相關的蛋白谷氨酸天冬氨酸轉運蛋白(GLAST)和谷氨酸轉運蛋白 1 (GLT-1)的表現量被下調，飲食調節改善了高脂飲食造成的 GLAST 和 GLT-1 的表現量下調。但是，口服抗糖尿病藥 pioglitazone 不能逆轉高脂飲食造成的 GLAST和 GLT-1 的表現量下調。綜合上述，飲食調節改善了星形膠質細胞的肥大和過程重塑，減輕了高脂飲食所造成的小鼠之星形膠質神經可塑性的相關蛋白表現下調可能是透過 IKKβ/NF-κB 這訊息傳遞路徑。

Patients with obesity have more risk than the health to develop depression. Dietary modification is the treatments for obesity. Previous studies showed that high-fat diet (60% of fat, HFD) feeding mice induced the activation of astrocytes and altered the pathology of astrocytes in the hippocampus. Moreover, our preliminary data showed an one-month period of dietary modification could improve the metabolic disorder in HFD-induced obese mice. However, the effect of dietary modification on alleviating the HFD-induced depressive-like behaviors and astrocytic abnormalities remains elusive. This study aims to examine whether improvement of metabolic disorder could relieve depression in HFD- induced obese mice. First, we fed the eight-week-old C57BL/6 mice with a 12-week HFD to induce obesity and depression. Our results showed that the body weights of HFD-fed mice were significantly increased in comparison with that of normal diet mice. HFD indeed induced depressive-like behavior. Then, we performed the dietary modification for an one-month period to obese mice with normal diet. The body weights of obese mice were reduced and depressive-like behaviors were reversed after one-month dietary modification. However, dietary modification had no effect on the HFD-induced upregulated level of glial fibrillary acidic protein (GFAP) in the ventral hippocampus of mice by western blot, but reversed the HFD-induced decreases in total process lengths and numbers of branch points of the astrocytes in the ventral hippocampal CA1 and CA3 regions of mice by analyzing the fine structure of the astrocytes. The levels of glutamate transporter 1 (GLT-1) and glutamate aspartate transporter (GLAST) were downregulated in HFD-induced obese mice and dietary modification reversed the HFD-induced l expression of GLT-1 and GLAST. However, pioglitazone (PIO) which is an oral antidiabetic drug could not reverse the HFD-induced suppressing expression of GLT-1 and GLAST. Moreover, we also found that HFD-induced upregulated expression of the phospho-IκB kinase (pIKK) /IκB kinase (IKK) in the ventral hippocampus was significantly decreased after the dietary modification for one month. In conclusion, , dietary modification had improvement of the hypertrophy and process remodeling of the astrocytes and alleviated the HFD-induced downregulated levels of GLAST and GLT-1 in astrocytes of mice partially through the IKKβ/NF-κB.

Abstract	I
Abstract in Chinese	II
致謝	IV
Content	V
Abbreviations	VIII
Introduction	1
1.	Diabetes Mellitus	2
1.1.	Epidemiology	2
1.2.	Types of DM	2
1.2.1.	Type 1 diabetes mellitus	2
1.2.2.	Type 2 diabetes mellitus	2
1.2.3.	Gestational diabetes mellitus (GDM)	3
1.3.	Medications of DM	3
1.3.1.	Medications of type 1 DM	3
1.3.2.	Medications of type 2 DM	4
2.	Depression	6
2.1.	Epidemiology	6
2.2.	Pathology of depression	6
2.2.1.	Synaptic plasticity	6
2.2.2.	Epigenetics	7
2.2.3.	Immune system	7
2.2.4.	Astrocyte	7
2.3.	Medications of depression	8
2.3.1.	Norepinephrine and/or serotonin and/or dopamine reuptake inhibitors	8
2.3.2.	Monoamine oxidase inhibitors (MAOIs)	8
3.	Association between diabetes mellitus and depression	8
3.1.	Epidemiology	9
3.2.	Underlying mechanisms between diabetes mellitus and depression	9
3.2.1.	Endocrine systems	9
3.2.2.	Neurological changes	10
4.	Related brain regions and neural pathways involved in depression	10
4.1.	Hypothalamic paraventricular nucleus (PVN)	10
4.2.	Prefrontal cortex (PFC)	11
4.3.	Hippocampus	11
4.3.1.	hippocampal astrocytes	11
4.3.2.	astrocytic glutamatergic transmission	12
4.3.3.	NFĸB pathway	12
Specific Aim	13
Materials and Methods	15
1.	Materials	16
2.	Recipes	18
3.	Methods	21
3.1.	Animals	21
3.2.	Open field test (OFT)	21
3.3.	Sucrose preference test (SPT)	21
3.4.	Tail suspension test (TST)	22
3.5.	Forced swimming test (FST)	22
3.6.	Brain preparation	22
3.7.	Immunohistochemistry	23
3.8.	Protein extraction and Western blot	23
3.9.	Analysis of astrocytic morphology	24
3.10.	Statistics	24
Results	26
Aim 1: To generate the high-fat diet-induced obesity and depressed mice.	27
Aim 2: To study whether dietary modification could reverse HFD-induced obesity and depressive-like behaviors.	28
Aim 3: To investigate whether dietary modification could reverse HFD-induced upregulated expression of glial fibrillary acidic protein (GFAP) in the hippocampus.	29
Aim 4: To investigate whether dietary modification could reverse the HFD-induced shortened total process lengths and decreased numbers of branch points of the astrocytes in the hippocampal CA1 and CA3 regions of mice .	29
Aim 5: To study whether dietary modification could reverse HFD-induced downregulated expression of neuronal plasticity-related protein in astrocyte.	30
Aim 6: To study whether pioglitazone could reverse HFD-induced downregulated expression of neuronal plasticity-related protein in astrocyte.	30
Aim 7: To study the underlying mechanism by which the dietary modification reversed the HFD-induced shortened astrocytic process plasticity and upregulated neuronal plasticity-related protein.	31
Conclusion and Discussion	32
References	35
Figures	39
Figure 1. Effects of 12-week’s high-fat-diet on the body weight, water intake and food intake in mice.	40
Figure 2. Effects of 12-week’s high-fat-diet on the depressive-like behaviors in mice.	42
Figure 3. Effects of 12-week’s high-fat-diet on the locomotor activities in mice.	43
Figure 4. Effects of 4-week’s dietary modification on the body weight, water intake and food intake in mice.	44
Figure 5. Effects of 4-week’s dietary modification on the depressive-like behaviors in mice.	46
Figure 6. Effects of 4-week’s dietary modification on the locomotor activities in mice.	47
Figure 7. Effects of 4-week’s dietary modification on the GFAP expression in the ventral hippocampus of mice.	48
Figure 8. Effects of 4-week’s dietary modification on fine structures in the hippocampal astrocyte.	49
Figure 9. Effect of 4-week’s dietary modification on expression of neuroplasticity-related proteins in the ventral hippocampus of mice.	51
Figure 10. Effect of pioglitazone on level of neuroplasticity-related proteins in the ventral hippocampus of mice.	52
                                    

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2026-08-18公開

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