Cardiac-specific overexpression of peroxisome proliferator-activated receptor-α causes insulin resistance in heart and liver
Cardiac-specific overexpression of peroxisome proliferator-activated receptor-α causes insulin resistance in heart and liver
复制标题
DOI：
10.2337/diabetes.54.9.2514
复制
发表时间：
2005-09-01
期刊：
影响因子：
7.7
通讯作者：
Kim, JK
中科院分区：
文献类型：
--
作者：
Park, SY;Cho, YR;Kim, JK
糖尿病心力衰竭可能与心脏能量代谢和胰岛素抵抗的改变有因果关系。心脏特异性过表达过氧化物酶体增殖物激活受体（PPAR）α的小鼠表现出与糖尿病心脏相似的代谢和心肌病表型;我们在清醒的肌球蛋白重链（MHC）-PPAR α小鼠（12-14周龄）的高胰岛素-正常血糖钳夹过程中测定了体内组织特异性葡萄糖代谢和胰岛素作用。MHC-PPAR α小鼠心脏基础和胰岛素刺激的葡萄糖摄取显著减少，心脏胰岛素抵抗主要归因于胰岛素受体底物（IRS）-1-相关磷脂酰肌醇（PI）3-激酶、Akt和信号转导和转录激活因子3（STAT 3）酪氨酸磷酸化的胰岛素刺激活性缺陷。有趣的是，MHC-PPARalpha小鼠出现了与胰岛素介导的IRS-2相关PI 3-激酶活性缺陷相关的肝脏胰岛素抵抗，肝脏甘油三酯和循环白细胞介素-6水平升高。为了确定潜在的机制，在8周龄的MHC-PPARalpha小鼠中进行胰岛素钳夹。与年龄匹配的野生型同窝小鼠相比，8周龄MHC-PPAR α小鼠的胰岛素刺激心脏葡萄糖摄取同样减少，而心脏功能和肝脏胰岛素作用没有变化。总体而言，这些发现表明，在糖尿病心脏中发生的PPAR α活性增加导致与胰岛素信号传导和STAT 3活性缺陷相关的心脏胰岛素抵抗;随后导致心脏功能降低。此外，年龄相关的肝脏胰岛素抵抗在MHC-PPAR α小鼠中发展，这可能是由于心脏代谢、功能和/或炎性细胞因子的改变。
Diabetic heart failure may be causally associated with alterations in cardiac energy metabolism and insulin resistance. Mice with heart-specific overexpression of peroxisome proliferator-activated receptor (PPAR)alpha showed a metabolic and cardiomyopathic phenotype similar to the diabetic heart; and we determined tissue-specific glucose metabolism and insulin action in vivo during hyperinsulinemic-euglycemic clamps in awake myosin heavy chain (MHC)-PPAR alpha mice (12-14 weeks of age). Basal and insulin-stimulated glucose uptake in heart was significantly reduced fin the MHC-PPAR alpha mice, and cardiac insulin resistance was mostly attributed to defects in insulin-stimulated activities of insulin receptor substrate (IRS)-1-associated phosphatidylinositol (PI) 3-kinase, Akt, and tyrosine phosphorylation of signal transducer and activator of transcription 3 (STAT3). Interestingly, MHC-PPAR alpha mice developed hepatic insulin resistance associated with defects in insulin-mediated IRS-2-associated PI 3-kinase activity, increased hepatic triglyceride, and circulating interleukin-6 levels. To determine the underlying mechanism, insulin clamps were conducted in 8-week-old MHC-PPAR alpha mice. Insulin-stimulated cardiac glucose uptake was similarly reduced in 8-week-old MHC-PPAR alpha mice without changes in cardiac function and hepatic insulin action compared with the age-matched wild-type littermates. Overall, these findings indicate that increased activity of PPAR alpha, as occurs in the diabetic heart, leads to cardiac insulin resistance associated with defects in insulin signaling and STAT3 activity; subsequently leading to reduced cardiac function. Additionally, age-associated hepatic insulin resistance develops in MHC-PPAR alpha mice that may be due to altered cardiac metabolism, functions, and/or inflammatory cytokines.