【摘要】：2型糖尿病和肥胖已經(jīng)成為當(dāng)今社會危害人類健康的常見代謝疾病,二者都是由于機體內(nèi)糖脂代謝紊亂所導(dǎo)致的,但是其發(fā)病的最根本機制至今還尚未明確,臨床上也沒有能夠治愈的方法。因此,探究2型糖尿病和肥胖的發(fā)病機制,并研發(fā)出安全有效的治療方案,是代謝領(lǐng)域亟需解決的問題。肌肉組織和脂肪組織在機體的能量代謝中都起著重要作用,它們既是機體最重要的產(chǎn)熱組織,又是機體糖脂代謝的關(guān)鍵器官。SIRT6是一種依賴于NAD+的去乙�；�,已經(jīng)被證實參與機體的多種代謝調(diào)控,但是關(guān)于其在肌肉組織和脂肪組織中的特異性作用,至今尚未明確。而鑒定SIRT6在這兩種組織中的調(diào)控作用將有利于為2型糖尿病和肥胖尋找治療靶點。我們分別構(gòu)建了肌肉組織特異性敲除SIRT6的小鼠模型和脂肪組織特異性敲除SIRT6的小鼠模型。我們采用肌肉組織特異性敲除SIRT6的小鼠進行了生理特征分析、代謝籠檢測和運動耐力測試等一系列實驗,并檢測了代謝相關(guān)蛋白和基因的表達水平,同時還在C2C12成肌細胞中驗證了 SIRT6在肌肉組織中的功能;我們采用脂肪組織特異性敲除SIRT6的小鼠進行了生理特征分析、氧耗測試、刺激誘導(dǎo)產(chǎn)熱等一系列實驗,還分離了脂肪原代細胞并誘導(dǎo)其分化,驗證SIRT6對脂肪組織的特異性調(diào)控,同時我們還探索了 SIRT6調(diào)控脂肪組織產(chǎn)熱的具體分子機制。通過研究我們發(fā)現(xiàn),肌肉組織特異性敲除SIRT6的小鼠機體的葡萄糖耐受性和胰島素敏感性受損,整體能量輸出減少,并且運動中的耐力減弱,原因是SIRT6的缺失降低了AMPK的活性,從而使其下游基因的表達量減少,導(dǎo)致骨骼肌細胞中葡萄糖和脂肪酸的攝入、脂肪酸氧化和線粒體氧化磷酸化作用被減弱,進而導(dǎo)致了機體的代謝紊亂;脂肪組織特異性敲除SIRT6的小鼠表現(xiàn)出明顯的肥胖,其棕色脂肪呈現(xiàn)“白色化”,血糖明顯升高,并伴隨胰島素抵抗和脂肪肝,整個機體氧耗減少,體溫降低,并且β-腎上腺素激動劑和冷刺激誘導(dǎo)的白色脂肪“棕色化”作用也明顯減弱。而SIRT6影響脂肪組織產(chǎn)熱的根本機制是SIRT6能夠與pATF2形成復(fù)合物而結(jié)合在產(chǎn)熱關(guān)鍵調(diào)節(jié)因子PGClα的啟動子區(qū),從而影響PGC1α和其下游產(chǎn)熱基因以及線粒體基因的表達,最終影響機體的能量輸出。我們的研究揭示了 SIRT6在肌肉組織和脂肪組織中通過發(fā)揮特異性作用,影響機體的糖脂代謝穩(wěn)態(tài)和能量平衡,為2型糖尿病和肥胖的治療提供了潛在的靶點。
[Abstract]:Type 2 diabetes mellitus and obesity have become the common metabolic diseases endangering human health. Both of them are caused by the disorder of glucose and lipid metabolism in the body, but the most basic mechanism of their pathogenesis has not been clarified. There is no cure clinically. Therefore, to explore the pathogenesis of type 2 diabetes and obesity and to develop safe and effective treatment is an urgent problem in the field of metabolism. Both muscle and adipose tissue play an important role in energy metabolism. They are not only the most important heat-producing tissue, but also the key organ of glycolipid metabolism. SIRT6 is a deacetylase dependent on NAD. It has been proved to be involved in a variety of metabolic regulation, but its specific role in muscle and adipose tissue has not been clarified. Identifying the regulatory role of SIRT6 in these two tissues will be helpful in finding therapeutic targets for type 2 diabetes and obesity. We constructed the mouse model of muscle-tissue specific knockout (SIRT6) and adipose tissue specific knockout (SIRT6). We used muscle-specific knockout SIRT6 mice to carry out a series of experiments, such as physiological characteristics analysis, metabolic cage test and exercise endurance test, and detected the expression level of metabolism-related proteins and genes. At the same time, the function of SIRT6 in muscle tissue was verified in C2C12 myoblasts. We used adipose tissue specific knockout SIRT6 mice for a series of experiments, such as physiological characteristics analysis, oxygen consumption test, stimulation induced heat production and so on. The primary adipocytes were isolated and induced to differentiate to verify the specific regulation of SIRT6 on adipose tissue. At the same time, we also explored the specific molecular mechanism of adipose tissue heat production regulated by SIRT6. We found that the glucose tolerance and insulin sensitivity of muscle-specific knockout SIRT6 mice were impaired, the overall energy output was reduced, and endurance during exercise was decreased, because the absence of SIRT6 reduced the activity of AMPK. Therefore, the expression of downstream genes was reduced, and the uptake of glucose and fatty acids in skeletal muscle cells, the oxidation of fatty acids and oxidative phosphorylation of mitochondria were weakened, which resulted in the metabolic disorder of the body. The mice with adipose tissue specific knockout of SIRT6 showed obvious obesity, their brown fat was "white", their blood glucose was significantly increased, and accompanied by insulin resistance and fatty liver, the whole body decreased oxygen consumption and hypothermia. 尾-adrenaline agonists and cold-stimulated white fat browning was also significantly weakened. However, the fundamental mechanism of SIRT6 affecting adipose tissue heat production is that SIRT6 can form complex with pATF2 and bind to the promoter region of PGCl 偽, which affects the expression of PGC1 偽, its downstream heat production gene and mitochondrial gene. Ultimately affect the body's energy output. Our study revealed that SIRT6 plays a specific role in muscle and adipose tissue, which affects the homeostasis and energy balance of glucose and lipid metabolism, and provides a potential target for the treatment of type 2 diabetes and obesity.
【學(xué)位授予單位】：北京協(xié)和醫(yī)學(xué)院
【學(xué)位級別】：博士
【學(xué)位授予年份】：2017
【分類號】：R587.1;R589.2

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