Targeting density-enhanced phosphatase-1 (DEP-1) with antisense oligonucleotides improves the metabolic phenotype in high-fat diet-fed mice
Targeting density-enhanced phosphatase-1 (DEP-1) with antisense oligonucleotides improves the metabolic phenotype in high-fat diet-fed mice
复制标题
用反义寡核苷酸靶向密度增强磷酸酶-1 (DEP-1) 可改善高脂肪饮食喂养小鼠的代谢表型
DOI：
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发表时间：
2013
影响因子：
8.4
通讯作者：
K. Kappert
中科院分区：
文献类型：
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作者：
Janine Krüger;Manuela Trappiel;M. Dagnell;P. Stawowy;H. Meyborg;Christian Böhm;S. Bhanot;A. Östman;U. Kintscher;K. Kappert
背景胰岛素信号转导是通过蛋白酪氨酸磷酸酶（PTPs）使胰岛素受体的酪氨酸去磷酸化而受到严格控制的。DEP-1是一种PTP，可使多种受体酪氨酸激酶中的酪氨酸残基去磷酸化。在这里，我们分析了DEP-1的活性是否差异调节肝脏，骨骼肌和脂肪组织下的高脂饮食（HFD），研究DEP-1在体内胰岛素抵抗的作用，其功能在insulin signaling.ResultsMice喂养了10周的HFD诱导肥胖相关的胰岛素抵抗。此后，对HFD小鼠进行针对DEP-1或对照ASO的特异性反义寡核苷酸（ASO）的全身施用，所述反义寡核苷酸在肝组织中高度累积。靶向DEP-1导致胰岛素敏感性改善，基础葡萄糖水平降低，体重显著减轻。这伴随着较低的胰岛素和瘦素血清水平。体内DEP-1的抑制也诱导肝脏胰岛素信号级联中的过度磷酸化。此外，DEP-1物理与胰岛素受体在原位，和重组DEP-1去磷酸化的胰岛素receptor in vitro.ConclusionsThese结果表明，DEP-1作为一种内源性拮抗剂的胰岛素受体，和下调DEP-1的结果在改善胰岛素敏感性。因此，DEP-1可能代表了一种新的目标，用于减轻代谢性疾病。
BackgroundInsulin signaling is tightly controlled by tyrosine dephosphorylation of the insulin receptor through protein-tyrosine-phosphatases (PTPs). DEP-1 is a PTP dephosphorylating tyrosine residues in a variety of receptor tyrosine kinases. Here, we analyzed whether DEP-1 activity is differentially regulated in liver, skeletal muscle and adipose tissue under high-fat diet (HFD), examined the role of DEP-1 in insulin resistance in vivo, and its function in insulin signaling.ResultsMice were fed an HFD for 10 weeks to induce obesity-associated insulin resistance. Thereafter, HFD mice were subjected to systemic administration of specific antisense oligonucleotides (ASOs), highly accumulating in hepatic tissue, against DEP-1 or control ASOs. Targeting DEP-1 led to improvement of insulin sensitivity, reduced basal glucose level, and significant reduction of body weight. This was accompanied by lower insulin and leptin serum levels. Suppression of DEP-1 in vivo also induced hyperphosphorylation in the insulin signaling cascade of the liver. Moreover, DEP-1 physically associated with the insulin receptor in situ, and recombinant DEP-1 dephosphorylated the insulin receptor in vitro.ConclusionsThese results indicate that DEP-1 acts as an endogenous antagonist of the insulin receptor, and downregulation of DEP-1 results in an improvement of insulin sensitivity. DEP-1 may therefore represent a novel target for attenuation of metabolic diseases.
影响因子：
15.9
作者：
Ahmad, F;Azevedo, JL;Goldstein, BJ
通讯作者：
Goldstein, BJ
影响因子：
4.8
作者：
M. Swarbrick;P. Havel;A. Levin;A. Bremer;K. Stanhope;M. Butler;S. Booten;J. Graham;R. Mckay;S. Murray;L. Watts;B. Monia;S. Bhanot
通讯作者：
M. Swarbrick;P. Havel;A. Levin;A. Bremer;K. Stanhope;M. Butler;S. Booten;J. Graham;R. Mckay;S. Murray;L. Watts;B. Monia;S. Bhanot
影响因子：
4.1
作者：
Tsuboi, Nobuo;Utsunomiya, Tadahiko;Takahashi, Takamune
通讯作者：
Takahashi, Takamune