Sakina Ali, Xavier Vidal-Gómez, Megan Piquet, Luisa Vergori, Gilles Simard, Séverine Dubois, Pierre-Henri Ducluzeau, Pascal Pomiès, Sarah Kamli-Salino, Mirela Delibégovic, Samir Henni, Frédéric Gagnadoux, Ramaroson Andriantsitohaina, M. Carmen Martínez
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EVs from IR participants expressed two types of phosphatases, phosphotyrosine 1 phosphatase (PTP1B) and protein phosphatase 2 (PP2A), IR lEVs being enriched with the active form of PTP1B while IR sEVs mainly carried active PP2A. Blockade of PTP1B activity in IR lEVs fully restored IRS1 and Akt phosphorylation in adipocytes and blunted insulin-induced Akt phosphorylation by inhibition of the macrophage secretome in hepatocytes. 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引用次数: 0
摘要
目的/假设与腹部肥胖、血脂异常、动脉高血压和高血糖相关的代谢紊乱是导致胰岛素抵抗的危险因素。方法分离并鉴定患有胰岛素抵抗（IR 组）和不患有胰岛素抵抗（n-IR 组）的小鼠体内的循环大 EVs（lEVs）和小 EVs（sEVs）。结果注射来自 IR 参与者的 lEVs 和 sEVs 会损害小鼠全身、脂肪组织和肝脏的胰岛素信号传导，而来自 n-IR 参与者的 EVs 则没有影响。此外，来自 IR 参与者的 lEVs 和 sEVs 使脂肪细胞体积和致脂肪基因表达量增加了两倍。IR 参与者的 EVs 表达两种类型的磷酸酶，即磷酸酪氨酸 1 磷酸酶（PTP1B）和蛋白磷酸酶 2（PP2A），IR lEVs 富含活性形式的 PTP1B，而 IR sEVs 主要携带活性 PP2A。阻断IR lEVs中PTP1B的活性可完全恢复脂肪细胞中IRS1和Akt的磷酸化，并通过抑制肝细胞中巨噬细胞分泌组来减弱胰岛素诱导的Akt磷酸化。相反，阻断 IR sEVs 中 PP2A 的活性可完全防止脂肪细胞和肝细胞中的胰岛素抵抗。结论/解释：这些数据表明，抑制 IR 参与者 EVs 所携带的磷酸酶可挽救脂肪细胞和肝细胞中的胰岛素信号，并指出 IR EVs 所携带的 PTP1B 和 PP2A 是防止脂肪组织和肝脏中的胰岛素抵抗以及肥胖症发展的新的潜在治疗靶点。
Circulating extracellular vesicle-carried PTP1B and PP2A phosphatases as regulators of insulin resistance
Aims/hypothesis
Metabolic disorders associated with abdominal obesity, dyslipidaemia, arterial hypertension and hyperglycaemia are risk factors for the development of insulin resistance. Extracellular vesicles (EVs) may play an important role in the regulation of metabolic signalling pathways in insulin resistance and associated complications.
Methods
Circulating large EVs (lEVs) and small EVs (sEVs) from individuals with (IR group) and without insulin resistance (n-IR group) were isolated and characterised. lEVs and sEVs were administered by i.v. injection to mice and systemic, adipose tissue and liver insulin signalling were analysed. The role of phosphatases was analysed in target tissues and cells.
Results
Injection of lEVs and sEVs from IR participants impaired systemic, adipose tissue and liver insulin signalling in mice, while EVs from n-IR participants had no effect. Moreover, lEVs and sEVs from IR participants brought about a twofold increase in adipocyte size and adipogenic gene expression. EVs from IR participants expressed two types of phosphatases, phosphotyrosine 1 phosphatase (PTP1B) and protein phosphatase 2 (PP2A), IR lEVs being enriched with the active form of PTP1B while IR sEVs mainly carried active PP2A. Blockade of PTP1B activity in IR lEVs fully restored IRS1 and Akt phosphorylation in adipocytes and blunted insulin-induced Akt phosphorylation by inhibition of the macrophage secretome in hepatocytes. Conversely, blockade of PP2A activity in IR sEVs completely prevented insulin resistance in adipocytes and hepatocytes.
Conclusions/interpretation
These data demonstrate that inhibition of phosphatases carried by EVs from IR participants rescues insulin signalling in adipocytes and hepatocytes and point towards PTP1B and PP2A carried by IR EVs as being novel potential therapeutic targets against insulin resistance in adipose tissue and liver and the development of obesity.
期刊介绍：
Diabetologia, the authoritative journal dedicated to diabetes research, holds high visibility through society membership, libraries, and social media. As the official journal of the European Association for the Study of Diabetes, it is ranked in the top quartile of the 2019 JCR Impact Factors in the Endocrinology & Metabolism category. The journal boasts dedicated and expert editorial teams committed to supporting authors throughout the peer review process.
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