Rapamycin negatively impacts insulin signaling, glucose uptake and uncoupling protein-1 in brown adipocytes
Rapamycin negatively impacts insulin signaling, glucose uptake and uncoupling protein-1 in brown adipocytes
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DOI：
10.1016/j.bbalip.2016.09.016
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发表时间：
2016-12-01
影响因子：
4.8
通讯作者：
Valverde, Angela M.
中科院分区：
文献类型：
--
作者：
Garcia-Casarrubios, Ester;de Moura, Carlos;Valverde, Angela M.
移植后新发糖尿病（NODAT）是一种代谢紊乱，40%的患者接受免疫抑制剂（IA）治疗，如雷帕霉素（也称为西罗莫司）。IAs负向调节包括骨骼肌、肝脏和白色脂肪在内的外周组织的胰岛素作用。然而，IAs对胰岛素敏感性和棕色脂肪组织（BAT）产热的影响尚未被研究。我们分析了雷帕霉素对BAT中胰岛素信号、产热基因表达和线粒体呼吸的影响。用雷帕霉素处理棕色脂肪细胞16小时可显著降低胰岛素受体底物1 （IRS1）蛋白表达和胰岛素介导的蛋白激酶B （Akt）磷酸化。因此，胰岛素诱导的葡萄糖转运蛋白4 （GLUT4）向质膜的易位和葡萄糖摄取都减少。还观察到n端Janus活化激酶（JNK）的早期活化，从而增加IRS1 Ser 307的磷酸化。雷帕霉素对棕色脂肪细胞胰岛素信号传导的这些影响被JNK抑制剂部分阻止。在体内用雷帕霉素治疗三周的大鼠可消除胰岛素介导的BAT中Ala磷酸化。雷帕霉素还能抑制褐色脂肪细胞中去甲肾上腺素（NE）诱导的脂肪分解、过氧化物酶体增殖物激活受体（PGC-1 α）和解偶联蛋白(UCP)-1的表达。重要的是，基底线粒体呼吸、质子泄漏和最大呼吸能力在雷帕霉素处理的棕色脂肪细胞中显著降低。总之，我们首次证明了棕色脂肪细胞作为雷帕霉素靶细胞的重要作用，提示BAT中的胰岛素抵抗可能在NODAT的发展中发挥重要作用。(C) 2016 Elsevier B.V.版权所有
New onset diabetes after transplantation (NODAT) is a metabolic disorder that affects 40% of patients on immunosuppressive agent (IA) treatment, such as rapamycin (also known as sirolimus). IAs negatively modulate insulin action in peripheral tissues including skeletal muscle, liver and white fat. However, the effects of IAs on insulin sensitivity and thermogenesis in brown adipose tissue (BAT) have not been investigated. We have analyzed the impact of rapamycin on insulin signaling, thermogenic gene-expression and mitochondria] respiration in BAT. Treatment of brown adipocytes with rapamycin for 16 h significantly decreased insulin receptor substrate 1 (IRS1) protein expression and insulin-mediated protein kinase B (Akt) phosphorylation. Consequently, both insulin-induced glucose transporter 4 (GLUT4) translocation to the plasma membrane and glucose uptake were decreased. Early activation of the N-terminal Janus activated kinase (JNK) was also observed, thereby increasing IRS1 Ser 307 phosphorylation. These effects of rapamycin on insulin signaling in brown adipocytes were partly prevented by a JNK inhibitor. In vivo treatment of rats with rapamycin for three weeks abolished insulin-mediated Ala phosphorylation in BAT. Rapamycin also inhibited norepinephrine (NE)-induced lipolysis, the expression of peroxisome proliferator-activated receptor)1 coactivator la (PGC-1 alpha) and uncoupling protein (UCP)-1 in brown adipocytes. Importantly, basal mitochondrial respiration, proton leak and maximal respiratory capacity were significantly decreased in brown adipocytes treated with rapamycin. In conclusion, we demonstrate, for the first time the important role of brown adipocytes as target cells of rapamycin, suggesting that insulin resistance in BAT might play a major role in NODAT development. (C) 2016 Elsevier B.V. All rights reserved.