Adipose tissue is required for the antidiabetic, but not for the hypolipidemic, effect of thiazolidinediones
Adipose tissue is required for the antidiabetic, but not for the hypolipidemic, effect of thiazolidinediones
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DOI：
10.1172/jci11245
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发表时间：
2000-11-01
影响因子：
15.9
通讯作者：
Reitman, ML
中科院分区：
文献类型：
--
作者：
Chao, L;Marcus-Samuels, B;Reitman, ML
抗糖尿病噻唑烷二酮类药物（TZDs）的作用部位尚不确定。这些药物是转录因子PPAR γ的激动剂配体，PPAR γ在脂肪组织中含量丰富，但在肝脏和肌肉中通常含量很低。我们研究了TZDs对缺乏白色脂肪组织的A-ZIP/F-1小鼠的影响。A-ZIP/F-1表型与患有严重脂肪萎缩性糖尿病的人惊人地相似，包括脂肪缺乏，明显的胰岛素抵抗和高血糖症，高脂血症和脂肪肝。罗格列酮或曲格列酮治疗并没有降低血糖或胰岛素水平，这表明白色脂肪组织是TZDs降糖作用所必需的。然而，在A-ZIP/F-1小鼠中，TZD治疗可有效降低循环甘油三酯和增加全身脂肪酸氧化，这表明这种作用是通过白色脂肪组织以外的靶点发生的。a - zip /F-1小鼠肝脏PPAR γ mRNA水平显著升高，这可能是脂肪肝的一般特性。罗格列酮治疗增加了A-ZIP/F-1和ob/ob小鼠脂肪变性肝脏的甘油三酯含量，但对脂肪移植的A-ZIP/F-1小鼠的“瘦”肝脏没有影响。鉴于有证据表明罗格列酮在脂肪变性肝中的作用不同，罗格列酮的影响，特别是对肝脏甘油三酯水平的影响，应在肝脂肪变性患者中进行检查。
There is uncertainty about the site(s) of action of the antidiabetic thiazolidinediones (TZDs). These drugs are agonist ligands of the transcription factor PPAR gamma, which is abundant in adipose tissue but is normally present at very low levels in liver and muscle. We have studied the effects of TZDs in A-ZIP/F-1 mice, which lack white adipose tissue. The A-ZIP/F-1 phenotype strikingly resembles that of humans with severe lipoatrophic diabetes, including the lack of fat, marked insulin resistance and hyperglycemia, hyperlipidemia, and fatty liver. Rosiglitazone or troglitazone treatment did not reduce glucose or insulin levels, suggesting that white adipose tissue is required for the antidiabetic effects of TZDs. However, TZD treatment was effective in lowering circulating triglycerides and increasing whole body fatty acid oxidation in the A-ZIP/F-1 mice, indicating that this effect occurs via targets other than white adipose tissue. A-ZIP/F-1 mice have markedly increased liver PPAR gamma mRNA levels, which may be a general property of fatty livers. Rosiglitazone treatment increased the triglyceride content of the steatotic Livers of A-ZIP/F-1 and ob/ob mice, but not the "lean" livers of fat-transplanted A-ZIP/F-1 mice. In light of this evidence that rosiglitazone acts differently in steatotic livers, the effects of rosiglitazone, particularly on hepatic triglyceride levels, should be examined in humans with hepatic steatosis.