NPV-BSK805, an Antineoplastic Jak2 Inhibitor Effective in Myeloproliferative Disorders, Causes Adiposity in Mice by Interfering With the Action of Leptin.
Front. Pharmacol.. 2018-05-15; 9:
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1. Front Pharmacol. 2018 May 15;9:527. doi: 10.3389/fphar.2018.00527. eCollection
NPV-BSK805, an Antineoplastic Jak2 Inhibitor Effective in Myeloproliferative
Disorders, Causes Adiposity in Mice by Interfering With the Action of Leptin.
Haissaguerre M(1)(2)(3), Ferriere A(1)(2)(3), Clark S(1)(2), Guzman-Quevedo
O(1)(2)(4), Tabarin A(1)(2)(3), Cota D(1)(2).
(1)INSERM, Neurocentre Magendie, Physiopathologie de la Plasticité Neuronale,
U1215, Bordeaux, France.
(2)University of Bordeaux, Neurocentre Magendie, Physiopathologie de la
Plasticité Neuronale, U1215, Bordeaux, France.
(3)Service d’Endocrinologie, Diabétologie et Nutrition, Hôpital Haut-Lévêque, CHU
de Bordeaux, Pessac, France.
(4)Facultad de Químico-Farmacobiología, Universidad Michoacána de San Nicolás de
Hidalgo, Morelia, Mexico.
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.