Ye Ji-Ming, Iglesias Miguel A, Watson David G, Ellis Bronwyn, Wood Leonie, Jensen Per Bo, Sørensen Rikke Veggerby, Larsen Philip Just, Cooney Gregory J, Wassermann Karsten, Kraegen Edward W
Diabetes and Obesity Program, Garvan Institute of Medical Research, Sydney, New South Wales 2010, Australia.
Am J Physiol Endocrinol Metab. 2003 Mar;284(3):E531-40. doi: 10.1152/ajpendo.00299.2002.
Peroxisome proliferator-activated receptor (PPAR)alpha and PPARgamma agonists lower lipid accumulation in muscle and liver by different mechanisms. We investigated whether benefits could be achieved on insulin sensitivity and lipid metabolism by the dual PPARalpha/gamma agonist ragaglitazar in high fat-fed rats. Ragaglitazar completely eliminated high-fat feeding-induced liver triglyceride accumulation and visceral adiposity, like the PPARalpha agonist Wy-14643 but without causing hepatomegaly. In contrast, the PPARgamma agonist rosiglitazone only slightly lessened liver triglyceride without affecting visceral adiposity. Compared with rosiglitazone or Wy-14643, ragaglitazar showed a much greater effect (79%, P < 0.05) to enhance insulin's suppression of hepatic glucose output. Whereas all three PPAR agonists lowered plasma triglyceride levels and lessened muscle long-chain acyl-CoAs, ragaglitazar and rosiglitazone had greater insulin-sensitizing action in muscle than Wy-14643, associated with a threefold increase in plasma adiponectin levels. There was a significant correlation of lipid content and insulin action in liver and particularly muscle with adiponectin levels (P < 0.01). We conclude that the PPARalpha/gamma agonist ragaglitazar has a therapeutic potential for insulin-resistant states as a PPARgamma ligand, with possible involvement of adiponectin. Additionally, it can counteract fatty liver, hepatic insulin resistance, and visceral adiposity generally associated with PPARalpha activation, but without hepatomegaly.
过氧化物酶体增殖物激活受体（PPAR）α和PPARγ激动剂通过不同机制降低肌肉和肝脏中的脂质蓄积。我们研究了双重PPARα/γ激动剂拉格列扎在高脂喂养大鼠中对胰岛素敏感性和脂质代谢是否有益。拉格列扎完全消除了高脂喂养诱导的肝脏甘油三酯蓄积和内脏肥胖，与PPARα激动剂Wy-14643相似，但不会引起肝肿大。相比之下，PPARγ激动剂罗格列酮仅略微降低肝脏甘油三酯，而不影响内脏肥胖。与罗格列酮或Wy-14643相比，拉格列扎在增强胰岛素对肝葡萄糖输出的抑制作用方面效果更佳（79%，P<0.05）。虽然所有三种PPAR激动剂均降低了血浆甘油三酯水平并减少了肌肉中的长链酰基辅酶A，但拉格列扎和罗格列酮在肌肉中的胰岛素增敏作用比Wy-14643更强，这与血浆脂联素水平增加三倍相关。肝脏尤其是肌肉中的脂质含量和胰岛素作用与脂联素水平存在显著相关性（P<0.01）。我们得出结论，PPARα/γ激动剂拉格列扎作为一种PPARγ配体，对胰岛素抵抗状态具有治疗潜力，可能与脂联素有关。此外，它可以对抗通常与PPARα激活相关的脂肪肝、肝脏胰岛素抵抗和内脏肥胖，但不会引起肝肿大。
