高脂肪飲食會造成肥胖，常伴隨周邊組織發炎與引發中樞神經系統下視丘調控食慾與能量代謝的重要區域之一，位於後腹(posterior)弓形核區微膠細胞與星狀膠細胞的活化和發炎反應。下視丘屬於專司情緒和學習記憶功能的邊緣系統(limbic system)。下視丘在神經內分泌參與Hypothalamic–pituitary–adrenal axis (HPA)調節情緒與壓力。因為膠細胞扮演大腦神經元細胞存活與維持環境穩定的重要角色，然而高脂飲食誘發的肥胖是否因為下視丘膠細胞活化，而產生情緒障礙並不清楚。因此，本研究首先建立高脂飼料餵食小鼠動物模式。餵食高脂飼料二個月小鼠體重顯著上升並伴隨肥胖體型產生，然而其每日平均攝食量與飲水量明顯減少。高脂飼料餵食也引發肥胖鼠下視丘後腹弓形核區和下方正中隆起組織的微膠細胞活化。然而，在飲食回復實驗發現將高脂飼料餵食一段時間後再改回一般飼料的給予，小鼠體重顯著下降，且其平均攝食量與飲水量回升，說明高脂飲食引起的體重增加是可逆性的。更進一步以穿透式電子顯微影像分析，發現餵食高脂飼料的小鼠下視丘後段組織髓鞘結構鬆散且髓鞘鹼性蛋白質表現量有下降趨勢，神經軸突直徑增加，粒線體結構膨脹且內部皺褶結構損壞。但是，將高脂飼料餵食改回攝取一般飼料後，與控制組下視丘後腹組織髓鞘結構並無明顯地差異，大都呈現緊緻的結構。另外一方面在長期餵食高脂飼料8個月期間給予3次細菌內毒素脂多醣腹腔注射引發周邊炎壓力實驗中和只給予高脂飼料組別相比體重無顯著差異。但是，動物行為測試分析發現同時給予高脂飼料與脂多醣腹腔注射的組別和給予一般飼料和脂多醣腹腔注射組別相比會產生焦慮和社交障礙行為的發展。綜合上述結果，高脂飼料可以誘發小鼠肥胖與下視丘微膠細胞活化伴隨下視丘後腹區髓鞘結構與粒線體結構的損壞。動物模式結果顯示，在長期高脂飲食過程伴隨多次周邊發炎壓力易引發焦慮和社交行為障礙。

To study the role of hypothalamic inflammation in mood disorder associated with high fat diet-induced obesity, we first established an animal model of obesity by feeding male C57BL/6 mice at 8 week old with high fat diet (HFD; 61.6% fat). The body weights of mice fed by HFD increased rapidly, but their food intake and water intake reduced significantly. When their diet was changed from HFD to the regular diet (Chow; 13.4% fat), the body weight, food intake and water intake of the animals were back to the level similar to that of the control group. Through immunofluroescence, activated Iba1+ microglia with an amoeboid form were observed in median eminence (ME) of the hypothalamus after HFD feeding. Using transmission electron microscope (TEM) analysis, the integrity of myelin in the posterior hypothalamus was impaired after HFD feeding for 4 months. However, diet reverse can prohibit impairment of hypothalamic myelin from HFD feeding. In addition, the hyperfused and the damaged cristae of mitochondria was observed in the posterior hypothalamus of HFD-fed mice. Furthermore, the intraperitoneal injection (i.p.) with lipopolysaccharide (LPS; dose 1 mg/kg per injection) at 1, 2 and 4 week during the period of 8-month HFD feeding was conducted. The body weights of HFD-fed mice receiving LPS injections was not different from that measured in HFD-fed mice receiving saline injections. At 8 month, the animals were subjected to a series of behavior analysis. The results indicated that HFD-fed mice receiving LPS injections developed anxiety-like and social impairing behaviors when compared to Chow-fed mice receiving LPS injections. In conclusion, we demonstrate that HFD feeding caused a damage in the integrity of mitochondria and myelin in the hypothalamic region nearby arcuate nucleus (ARC), a place with the accumulation of activated microglia. In addition, chronic HFD feeding combined with repeated peripheral LPS injection developed in anxiety and impaired social interaction in mice.

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