肥胖會增加罹患第二型糖尿病的風險。高脂飲食導致肥胖和增加血液中的游離脂肪酸，當游離脂肪酸堆積在肌肉組織可能會造成胰島素抗性。粒線體功能異常和胰島素抗性被認為是發展成第二型糖尿病的原因。粒線體的動態平衡，藉由融合 (fusion)的分子─mitofusins (Mfn1 和 Mfn2) 及optic atrophy type 1 (Opa1)，與分裂(fission)的分子─dynamin-related protein 1 (Drp1) 和Fis1能夠控制粒線體的形態。粒線體的動態平衡維繫著粒線體和細胞的功能，擾亂此平衡關係會導致粒線體功能異常和細胞死亡。在過去文獻也指出，在肥胖和第二型糖尿病中，觀察到粒線體變小，數目較少且內部形態呈現有空泡等改變，以及粒線體功能的降低。因此我們假設高脂所導致的粒線體動態平衡的改變是造成粒線體功能異常的原因。我們利用棕櫚酸 (palmitate) 模擬在高脂的刺激下，分化的肌肉細胞 (C2C12 cells) 會產生粒線體斷裂，接著伴隨粒線體膜電位的下降。粒線體的斷裂可能透過粒線體分裂增加或是融合減少，也有可能兩者同時發生。利用轉染的方式，單獨增加調控粒線體融合蛋白Mfn1 或 Mfn2無法改善棕櫚酸造成的粒線體斷裂；而增加失去粒線體分裂活性的蛋白Drp1-DN，可以抑制棕櫚酸導致粒線體的斷裂和粒線體膜電位的降低。另外，我們發現5-aminoimidazole-4-carboxamide ribonucleotide (AICAR) 可透過AMP-activated protein kinase (AMPK)活化，增加pgc1a、mfn1、mfn2、opa1以及drp1的基因表現。經由AICAR的給予，可以減少棕櫚酸造成粒線體斷裂及粒線體膜電位的下降。綜合以上結果，棕櫚酸造成的粒線體斷裂，會進一步導致粒線體功能異常，然而只要阻斷粒線體斷裂就可以恢復粒線體功能。我們認為當過多的脂質堆積在骨骼肌中，可能會造成粒線體動態平衡的失衡，而導致粒線體功能異常和胰島素抗性。所以調控粒線體動態平衡，可作為治療的方向，減緩代謝相關疾病的進程。

Obese people have high risk of type 2 diabetes. High fat diet increase free fatty acid in circulation, and accumulation of fatty acid in skeletal muscle leads to insulin resistance. Previous reports showed that mitochondrial dysfunction and insulin resistance are involved in the development of type 2 diabetes. Mitochondrial dynamics, including both fusion and fission of mitochondria, exchange the contents of mitochondria and control mitochondrial morphology. Mitochondrial fusion is controlled by mitofusins (Mfn1 or Mfn2) and optic atrophy type 1 (Opa1), whereas mitochondrial fission is controlled by dynamin-related protein 1 (Drp1) and Fis1. Mitochondrial dynamics is important for many mitochondrial and cellular functions, and disruption of this balance results in mitochondrial dysfunction and cell death. Recent studies showed that muscle from obese subjects or from type 2 diabetic patients exhibited reductions of mitochondrial function and size, compared to those from lean volunteers. Therefore, we hypothesize that excess fat shifts the balance of mitochondrial dynamics, further contributing to mitochondrial dysfunction. We treated differential C2C12 muscle cells with palmitate to mimic the high fat condition. Palmitate changed mitochondrial morphology toward fission and decreased mitochondrial membrane potential in C2C12 cells. Because mitochondrial fragmentation can result from decreased mitochondrial fusion or increased mitochondrial fission, we transfected plasmids to affect the balance of mitochondrial fusion/fission in C2C12 cells. Overexpression of Mfn1 or Mfn2 did not affect palmitate-induced mitochondrial fragmentation. However, overexpression of Drp1-K38A, a dominant-mutant form of Drp1, ameliorated palmitate- induced mitochondrial fragmentation and reduction of mitochondrial membrane potential. Furthermore, AICAR increased AMPK phosphoryation and expressions of pgc1a, mfn1, mfn2, opa1 and drp1 in C2C12 cells. Treatment of AICAR partially attenuated mitochondrial fragmentation and completely inhibited reduction of mitochondrial membrane potential caused by palmitate. Thus, these results suggest that palmitate shifts the balance of mitochondrial dynamics toward fission and results in mitochondrial dysfunction, and blockade of mitochondrial fragmentation restores mitochondrial function. Accumulation of lipid in skeletal muscle may cause imbalance of mitochondrial dynamics, leading to mitochondrial dysfunction and insulin resistance. Our study suggests that modulation of mitochondrial dynamics may provide a therapeutic strategy for treating metabolism related disease, such as obesity, type 2 diabetes, and metabolic syndrome.

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