Regulation of energy metabolism by the insulin receptor substrate Dok-1

胰岛素受体底物(IRS)-1和IRS-2在胰岛素的作用中起主导作用，但胰岛素受体激酶的其他底物，如GAB1、c-CB1、SH2-B和APS也具有生理意义。虽然已知酪氨酸激酶-1(Dok1)下游的蛋白在胰岛素信号转导中作为多位点适配分子发挥作用，但它在能量平衡中的作用尚不清楚。我们在这里展示了Dok1调节肥胖的作用。在喂食高脂饮食的小鼠中，白色脂肪组织中Dok1的表达显著增加，而缺乏该接头的脂肪细胞较小，对这种饮食操作表现出较低的肥大反应。与野生型小鼠相比，Dok1基因缺陷小鼠更瘦，表现出更好的糖耐量和胰岛素敏感性。Dok1基因缺陷小鼠的胚胎成纤维细胞在成脂分化过程中受到损害，这种缺陷伴随着蛋白激酶ERK活性的增加以及随之而来的过氧化体增殖物激活受体(PPAR)-γ在Ser112上的磷酸化增加。PPAR-γ反式激活活性的这个负调控位点的突变阻止了Dok1消融引起的瘦肉型的发展。这些结果表明，DOK1通过拮抗ERK对PPAR-γ的抑制作用而促进脂肪细胞肥大，从而促进饮食诱导肥胖的发生。

Insulin receptor substrate (IRS)-1 and IRS-2 have dominant roles in the action of insulin, but other substrates of the insulin receptor kinase, such as Gab1, c-Cb1, SH2-B and APS, are also of physiological relevance. Although the protein downstream of tyrosine kinases-1 (Dok1) is known to function as a multisite adapter molecule in insulin signaling, its role in energy homeostasis has remained unclear. Here we show that Dok1 regulates adiposity. Expression of Dok1 in white adipose tissue was markedly increased in mice fed a high-fat diet, whereas adipocytes lacking this adapter were smaller and showed a reduced hypertrophic response to this dietary manipulation. Dok1-deficient mice were leaner and showed improved glucose tolerance and insulin sensitivity compared with wild-type mice. Embryonic fibroblasts from Dok1-deficient mice were impaired in adipogenic differentiation, and this defect was accompanied by an increased activity of the protein kinase ERK and a consequent increase in the phosphorylation of peroxisome proliferator-activated receptor (PPAR) -gamma on Ser 112. Mutation of this negative regulatory site for the transactivation activity of PPAR-gamma blocked development of the lean phenotype caused by Dok1 ablation. These results indicate that Dok1 promotes adipocyte hypertrophy by counteracting the inhibitory effect of ERK on PPAR-gamma and may thus confer predisposition to diet-induced obesity.