Fat cell-specific ablation of rictor in mice impairs insulin-regulated fat cell and whole-body glucose and lipid metabolism.
Fat cell-specific ablation of rictor in mice impairs insulin-regulated fat cell and whole-body glucose and lipid metabolism.
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作者：
Kumar A;Lawrence JC Jr;Jung DY;Ko HJ;Keller SR;Kim JK;Magnuson MA;Harris TE
Rictor是哺乳动物雷帕霉素靶蛋白（mTOR）复合物（mTORC）2的重要组成部分，mTORC 2是一种磷酸化和激活Akt的激酶，Akt是一种调节脂肪组织、骨骼肌和肝脏中葡萄糖和脂质代谢的胰岛素信号传导中间体。为了确定rictor/mTORC 2在胰岛素信号传导和脂肪细胞中的作用中的生理作用，我们开发了脂肪细胞特异性rictor敲除（FRic−/−）小鼠。在FRic−/−脂肪细胞中研究了胰岛素信号传导以及葡萄糖和脂质代谢。体内葡萄糖代谢通过高胰岛素-正葡萄糖钳夹来评估。脂肪细胞中rictor的缺失阻止了胰岛素刺激的Akt在S473处的磷酸化，这反过来又损害了下游靶点如T32处的FoxO 3a和T642处的AS 160的磷酸化。然而，S9处的糖原合成酶激酶-3 β磷酸化不受影响。FRic−/−脂肪细胞中的信号缺陷导致胰岛素刺激的GLUT 4向质膜的转运受损，葡萄糖转运减少。此外，无rictor的脂肪细胞不能抑制响应于胰岛素的脂解，导致循环游离脂肪酸和甘油升高。这些代谢紊乱可能是在FRic−/−小鼠全身水平观察到的缺陷的原因，包括葡萄糖耐受不良、显著的高胰岛素血症、骨骼肌和肝脏的胰岛素抵抗以及肝脏脂肪变性。脂肪细胞中的Rictor/mTORC 2通过介导调节脂肪细胞中葡萄糖和脂质代谢所必需的信号传导在全身能量稳态中起重要作用。
Rictor is an essential component of mammalian target of rapamycin (mTOR) complex (mTORC) 2, a kinase that phosphorylates and activates Akt, an insulin signaling intermediary that regulates glucose and lipid metabolism in adipose tissue, skeletal muscle, and liver. To determine the physiological role of rictor/mTORC2 in insulin signaling and action in fat cells, we developed fat cell–specific rictor knockout (FRic−/−) mice. Insulin signaling and glucose and lipid metabolism were studied in FRic−/− fat cells. In vivo glucose metabolism was evaluated by hyperinsulinemic-euglycemic clamp. Loss of rictor in fat cells prevents insulin-stimulated phosphorylation of Akt at S473, which, in turn, impairs the phosphorylation of downstream targets such as FoxO3a at T32 and AS160 at T642. However, glycogen synthase kinase-3β phosphorylation at S9 is not affected. The signaling defects in FRic−/− fat cells lead to impaired insulin-stimulated GLUT4 translocation to the plasma membrane and decreased glucose transport. Furthermore, rictor-null fat cells are unable to suppress lipolysis in response to insulin, leading to elevated circulating free fatty acids and glycerol. These metabolic perturbations are likely to account for defects observed at the whole-body level of FRic−/− mice, including glucose intolerance, marked hyperinsulinemia, insulin resistance in skeletal muscle and liver, and hepatic steatosis. Rictor/mTORC2 in fat cells plays an important role in whole-body energy homeostasis by mediating signaling necessary for the regulation of glucose and lipid metabolism in fat cells.