Effect of heterozygous PPARγ deficiency and TZD treatment on insulin resistance associated with age and high-fat feeding
Effect of heterozygous PPARγ deficiency and TZD treatment on insulin resistance associated with age and high-fat feeding
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DOI：
10.1152/ajpendo.00312.2002
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发表时间：
2003-03-01
影响因子：
5.1
通讯作者：
Olefsky, JM
中科院分区：
文献类型：
--
作者：
Miles, PDG;Barak, Y;Olefsky, JM
过氧化物酶体增殖物激活受体-γ (PPAR-) 是噻唑烷二酮 (TZD) 化合物的靶受体，TZD 是一类用于治疗 2 型糖尿病的胰岛素增敏药物。然而，矛盾的是，缺乏 PPARgamma (PPARgamma(+/-)) 的小鼠比其野生型 (WT) 同窝小鼠对胰岛素更敏感，而不是像预测的那样更敏感。为了确定 PPARgamma 缺乏是否可以阻止与年龄增长或高脂肪 (HF) 喂养相关的胰岛素抵抗的发展，对 2、4 和 8 月龄的 PPARgamma(+/-) 和 WT 小鼠以及饲喂 HF 饮食的动物的胰岛素敏感性进行了评估。由于 TZD 通过 PPARγ 受体发挥作用，因此我们还研究了曲格列酮（TZD）在这些小鼠中的作用。通过高胰岛素正常血糖钳夹和口服葡萄糖耐量试验评估葡萄糖代谢。两组的胰岛素敏感性都随着年龄的增长而下降。然而，PPARgamma(+/-) 动物的下降幅度明显小于 WT 动物，因此，到 8 个月大时，PPARgamma(+/-) 小鼠的胰岛素敏感性明显高于 WT 小鼠。 TZD 治疗后 PPARgamma(+/-) 小鼠的这种较高敏感性消失了。高频喂养导致 WT 小鼠以及 PPARgamma(+/-) 小鼠显着的脂肪细胞肥大和外周组织以及肝脏胰岛素抵抗。用曲格列酮治疗这些小鼠完全阻止了脂肪细胞肥大和胰岛素作用正常化。总之，PPARgamma 缺乏可以部分预防与年龄相关的胰岛素抵抗，但不能预防 HF 饮食引起的胰岛素抵抗。
Peroxisome proliferator-activated receptor-gamma (PPAR-) is the target receptor for thiazolidinedione (TZD) compounds, which are a class of insulin-sensitizing drugs used in the treatment of type 2 diabetes. Paradoxically, however, mice deficient in PPARgamma (PPARgamma(+/-)) are more insulin sensitive than their wild-type (WT) littermates, not less, as would be predicted. To determine whether PPARgamma deficiency could prevent the development of the insulin resistance associated with increasing age or high-fat (HF) feeding, insulin sensitivity was assessed in PPARgamma(+/-) and WT mice at 2, 4, and 8 mo of age and in animals fed an HF diet. Because TZDs elicit their effect through PPARgamma receptor, we also examined the effect of troglitazone (a TZD) in these mice. Glucose metabolism was assessed by hyperinsulinemic euglycemic clamp and oral glucose tolerance test. Insulin sensitivity declined with age for both groups. However, the decline in the PPARgamma(+/-) animals was substantially less than that of the WT animals, such that, by 8 mo of age, the PPARgamma(+/-) mice were markedly more insulin sensitive than the WT mice. This greater sensitivity in PPARgamma(+/-) mice was lost with TZD treatment. HF feeding led to marked adipocyte hypertrophy and peripheral tissue and hepatic insulin resistance in WT mice but also in PPARgamma(+/-) mice. Treatment of these mice with troglitazone completely prevented the adipocyte hypertrophy and normalized insulin action. In conclusion, PPARgamma deficiency partially protects against age-related insulin resistance but does not protect against HF diet-induced insulin resistance.