Muscle-specific PPARgamma-deficient mice develop increased adiposity and insulin resistance but respond to thiazolidinediones.
Muscle-specific PPARgamma-deficient mice develop increased adiposity and insulin resistance but respond to thiazolidinediones.
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DOI：
10.1172/jci17305
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发表时间：
2003-08
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影响因子：
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通讯作者：
A. Norris;Lihong Chen;S. Fisher;I. Szanto;M. Ristow;A. Jozsi;M. Hirshman;E. Rosen;L. Goodyear;F. Gonzalez;B. Spiegelman;C. Kahn
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文献类型：
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作者：
A. Norris;Lihong Chen;S. Fisher;I. Szanto;M. Ristow;A. Jozsi;M. Hirshman;E. Rosen;L. Goodyear;F. Gonzalez;B. Spiegelman;C. Kahn
噻唑烷二酮类 (TZD) 激活过氧化物酶体增殖物激活受体 γ (PPARgamma)，通过增加骨骼肌中胰岛素刺激的葡萄糖处理来改善胰岛素抵抗。 TZD 对肌肉的影响是直接的还是通过脂肪组织间接的仍然存在争议。因此，我们使用 Cre/loxP 重组产生了肌肉特异性 PPARgamma 敲除 (MuPPARgammaKO) 的小鼠。有趣的是，尽管饮食摄入量减少，MuPPARgammaKO 小鼠仍出现过度肥胖。尽管肌肉中胰岛素刺激的葡萄糖摄取并未受损，但 MuPPARgammaKO 小鼠出现全身胰岛素抵抗，在高胰岛素钳夹期间维持血糖正常所需的葡萄糖输注速率降低了 36% (P < 0.05)，这主要是由于肝脏胰岛素作用的严重受损。当接受高脂肪饮食时，MuPPARgammaKO 小鼠会出现与对照组相同的高胰岛素血症和葡萄糖稳态受损。同时使用 TZD 治疗可以将 MuPPARgammaKO 小鼠的这些高脂肪诱导的缺陷改善到与对照组相同的程度。 MuPPARgammaKO 小鼠肌肉中几种脂质代谢基因的表达也发生了改变。因此，肌肉 PPARgamma 不是 TZD 的抗糖尿病作用所必需的，但在维持正常肥胖、全身胰岛素敏感性和肝脏胰岛素作用方面具有迄今为止未被怀疑的作用。介导这些效应的组织串扰可能是由于肌肉中脂质代谢的改变所致。
Activation of peroxisome proliferator-activated receptor gamma (PPARgamma) by thiazolidinediones (TZDs) improves insulin resistance by increasing insulin-stimulated glucose disposal in skeletal muscle. It remains debatable whether the effect of TZDs on muscle is direct or indirect via adipose tissue. We therefore generated mice with muscle-specific PPARgamma knockout (MuPPARgammaKO) using Cre/loxP recombination. Interestingly, MuPPARgammaKO mice developed excess adiposity despite reduced dietary intake. Although insulin-stimulated glucose uptake in muscle was not impaired, MuPPARgammaKO mice had whole-body insulin resistance with a 36% reduction (P < 0.05) in the glucose infusion rate required to maintain euglycemia during hyperinsulinemic clamp, primarily due to dramatic impairment in hepatic insulin action. When placed on a high-fat diet, MuPPARgammaKO mice developed hyperinsulinemia and impaired glucose homeostasis identical to controls. Simultaneous treatment with TZD ameliorated these high fat-induced defects in MuPPARgammaKO mice to a degree identical to controls. There was also altered expression of several lipid metabolism genes in the muscle of MuPPARgammaKO mice. Thus, muscle PPARgamma is not required for the antidiabetic effects of TZDs, but has a hitherto unsuspected role for maintenance of normal adiposity, whole-body insulin sensitivity, and hepatic insulin action. The tissue crosstalk mediating these effects is perhaps due to altered lipid metabolism in muscle.