在分化的3T3-L1脂肪細胞中高劑量胰島素造成脂肪激素和脂肪酸生成的差異性調控

前人的研究文獻明確指出肥胖造成心血管的疾病與第二型糖尿病的發生有極顯著的關連性。脂肪組織不僅是動物體內主要的能量儲藏場所，也具分泌脂肪細胞激素的功能，更可調控體內的能量平衡與代謝反應。最近的研究文獻顯示，脂肪組織會發生巨噬細胞浸潤 (infiltration) 的情形，進而影響體內的生理功能。為了研究胰島素對脂肪細胞功能之影響，本論文利用建立分化成熟的3T3-L1 脂肪細胞，探討胰島素處理對發炎因子及 adipocykine 表達的調控，我們也進一步研究活化的巨噬細胞分泌的因子是否會影響胰島素對脂肪細胞表達 adipokines 及發炎因子的調控。由本論文的結果顯示，3T3-L1 脂肪細胞以高劑量胰島素或高劑量葡萄糖合併胰島素處理，可造成三酸甘油酯大量堆積在脂肪細胞內，同時也促進了 TNF-α、IL-6、MCP-1、瘦體素和脂締素的生成，。當加入巨噬細胞 conditioned medium 時，刺激產生更多的 IL-6 及 MCP-1，減少脂締素的分泌。脂肪合成的轉錄因子 PPARγ，其主要的功能為調控脂質的生成與代謝，當3T3-L1 脂肪細胞處理高劑量胰島素及高劑量葡萄糖併用胰島素時，PPARγ 表現量會增加，相對的3T3-L1 脂肪細胞加入巨噬細胞 conditioned medium 時， PPARγ 表現量會下降，影響細胞內脂肪的合成及減少脂肪酸合成酶的生成，促進脂肪分解 (lipolysis)，引起脂肪組織發炎。是否造成胰島素拮抗 (insulin resistance) 的問題，則是需要後續實驗證明。本論文之研究建立的實驗模式未來可應用於肥胖、脂肪生成與代謝的相關研究，也可利用此建立之模式為平台，找尋治療糖尿病之藥物。

關鍵字

胰島素拮抗；脂肪；發炎；第二型糖尿病

並列摘要

Obesity is strongly associated with the development of cardiovascular diseases and type 2 diabetes mellitus. Adipocytes are not only an energy reservoir but also endocrine cells, which can secrete a variety of bioactive molecules called adipokines, and play crucial role in regulation of energy balance and metabolism. Recent studies suggest that macrophages can infiltrate into adipose tissues, and cause adipose tissue dysfunction. To address the effect of insulin on the biological functions of adipocyte, an established cell model, differentiated 3T3-L1 adipocytes were used. Additionally, the effects of macrophage secreted factors on the expression of adipokines and cytokines in both untreated and insulin-treated 3T3-L1 cells were also examined. Our results showed that treatment with high insulin or high insulin plus high glucose could significantly increase TNF-α, IL-6, MCP-1, adiponectin and leptin production, as well as fatty acid accumulation. Co-culture of 3T3-L1 adipocytes with macrophage conditioned-medium and insulin caused a significantly increase of IL-6 and MCP-1 production, but decrease of adiponectin production. Peroxisome proliferator-activated receptor-γ (PPAR-γ) regulates adipocyte genes involved in adipogenesis and lipid metabolism. 3T3-L1 adipocytes cultured with macrophage conditioned medium resulted in decrease of PPARγ expression, with subsequent reduction of fatty acid synthase production. These findings indicated that certain macrophage-secreted molecules might induce adipocyte-mediated inflammation, and obesity not only induces insulin resistance and type 2 diabetes mellitus, but also provokes serious inflammatory reactions. The established adipocyte cell model can be used to examine the obesity, lipogenesis and metabolism related studies. Besides, this model also can be used as a platform to screen therapeutic drugs for treatment of diabetes mellitus.

並列關鍵字

Insulin resistance ； Adipocyte ； Inflammation ； Type 2 diabetes mellitus

參考文獻

Adochio, R., J. W. Leitner, et al. (2009). "Rescuing 3T3-L1 adipocytes from insulin resistance induced by stimulation of Akt-mammalian target of rapamycin/p70 S6 kinase (S6K1) pathway and serine phosphorylation of insulin receptor substrate-1: effect of reduced expression of p85alpha subunit of phosphatidylinositol 3-kinase and S6K1 kinase." Endocrinology 150(3): 1165-73.

Google Scholar

Ambati, S., H. K. Kim, et al. (2007). "Effects of leptin on apoptosis and adipogenesis in 3T3-L1 adipocytes." Biochem Pharmacol 73(3): 378-84.

Google Scholar

Ahren, B. and P. J. Havel (1999). "Leptin inhibits insulin secretion induced by cellular cAMP in a pancreatic B cell line (INS-1 cells)." Am J Physiol 277(4 Pt 2): R959-66.

Google Scholar

Bhonagiri, P., G. R. Pattar, et al. (2009). "Hexosamine biosynthesis pathway flux contributes to insulin resistance via altering membrane phosphatidylinositol 4,5-bisphosphate and cortical filamentous actin." Endocrinology 150(4): 1636-45.

Google Scholar

Blumer, R. M., C. P. van Roomen, et al. (2008). "Regulation of adiponectin secretion by insulin and amino acids in 3T3-L1 adipocytes." Metabolism 57(12): 1655-62

Google Scholar

國際替代計量

在分化的3T3-L1脂肪細胞中高劑量胰島素造成脂肪激素和脂肪酸生成的差異性調控

全文下載

主題瀏覽