Haissaguerre Magalie, Ferriere Amandine, Clark Samantha, Guzman-Quevedo Omar, Tabarin Antoine, Cota Daniela
INSERM, Neurocentre Magendie, Physiopathologie de la Plasticité Neuronale, U1215, Bordeaux, France.
University of Bordeaux, Neurocentre Magendie, Physiopathologie de la Plasticité Neuronale, U1215, Bordeaux, France.
Front Pharmacol. 2018 May 15;9:527. doi: 10.3389/fphar.2018.00527. eCollection 2018.
The pathophysiology of body weight gain that is observed in patients suffering from myeloproliferative neoplasms treated with inhibitors of the janus kinase (Jak) 1 and 2 pathway remains unknown. Here we hypothesized that this class of drugs interferes with the metabolic actions of leptin, as this hormone requires functional Jak2 signaling. To test this, C57BL/6J chow-fed mice received either chronic intraperitoneal (ip) or repeated intracerebroventricular (icv) administration of the selective Jak2 inhibitor NVP-BSK805, which was proven efficacious in treating polycythemia in rodents. Changes in food intake, body weight and body composition were recorded. Icv NVP-BSK805 was combined with ip leptin to evaluate ability to interfere with the action of this hormone on food intake and on induction of hypothalamic phosphorylation of signal transducer and activator of transcription 3 (STAT3). We found that chronic peripheral administration of NVP-BSK805 did not alter food intake, but increased fat mass and feed efficiency. The increase in fat mass was more pronounced during repeated icv administration of the compound, suggesting that metabolic effects were related to molecular interference in brain structures regulating energy balance. Accordingly, acute icv administration of NVP-BSK805 prevented the ability of leptin to decrease food intake and body weight by impeding STAT3 phosphorylation within the hypothalamus. Consequently, acute icv administration of NVP-BSK805 at higher dose induced hyperphagia and body weight gain. Our results provide evidence for a specific anabolic effect exerted by antineoplastic drugs targeting the Jak2 pathway, which is due to interference with the actions of leptin. Consequently, assessment of metabolic variables related to increased fat mass gain should be performed in patients treated with Jak2 inhibitors.
在接受Janus激酶（Jak）1和2通路抑制剂治疗的骨髓增殖性肿瘤患者中观察到体重增加的病理生理机制仍不清楚。在此，我们假设这类药物会干扰瘦素的代谢作用，因为该激素需要功能性的Jak2信号传导。为了验证这一点，给食用普通饲料的C57BL/6J小鼠进行慢性腹腔内（ip）或反复脑室内（icv）注射选择性Jak2抑制剂NVP-BSK805，该抑制剂已被证明对治疗啮齿动物的红细胞增多症有效。记录食物摄入量、体重和身体组成的变化。将icv NVP-BSK805与ip瘦素联合使用，以评估其干扰该激素对食物摄入量以及对下丘脑信号转导和转录激活因子3（STAT3）磷酸化诱导作用的能力。我们发现，NVP-BSK805的慢性外周给药并未改变食物摄入量，但增加了脂肪量和饲料效率。在反复icv给药该化合物期间，脂肪量的增加更为明显，这表明代谢效应与调节能量平衡的脑结构中的分子干扰有关。因此，急性icv给药NVP-BSK805通过阻碍下丘脑内的STAT3磷酸化，阻止了瘦素降低食物摄入量和体重的能力。因此，高剂量急性icv给药NVP-BSK805会导致食欲亢进和体重增加。我们的结果为靶向Jak2通路的抗肿瘤药物产生的特定合成代谢作用提供了证据，这是由于干扰了瘦素的作用。因此，在接受Jak2抑制剂治疗的患者中，应评估与脂肪量增加相关的代谢变量。
