The Role of the tyrosine kinase Tyk2 in regulation of obesity

描述（由申请人提供）：Janus激酶Tyk2在控制参与免疫应答、细胞转化和维持体内平衡的基因表达方面起着关键作用。本研究的结果确定了Tyk2作为棕色脂肪细胞分化的关键介质的新功能。不表达Tyk2的小鼠会变得肥胖，并且在棕色脂肪细胞特异性基因表达方面存在缺陷。此外，高脂肪饮食的老鼠和肥胖的人骨骼肌中Tyk2的表达降低。Tyk2-/-前脂肪细胞在体外和转基因动物中的分化是通过Tyk2的表达，以及不能被细胞因子激活的激酶失活形式的酶来挽救的。此外，在细胞核中有一个Tyk2库，它与棕色脂肪组织（BAT）分化所需的转录因子相互作用。我们建议通过实验来了解Tyk2表达调控BAT分化和防止肥胖发展的机制。

DESCRIPTION (provided by applicant): The Janus kinase, Tyk2, plays a pivotal role in controlling the expression of genes involved in immune responses, cell transformation and maintaining homeostasis. Results in this proposal define a new function for Tyk2 as a key mediator of brown adipocyte differentiation. Mice that do not express Tyk2 become obese and have a defect in brown fat cell-specific gene expression. Furthermore, mice placed on a high fat diet and obese humans show decreased expression of Tyk2 in skeletal muscle. Differentiation of Tyk2-/- preadipocytes in vitro and in transgenic animals is rescued by the expression of Tyk2, as well as a kinase-inactive form of the enzyme that cannot be activated by cytokines. Furthermore, there is a pool of Tyk2 in the nucleus that interacts with transcription factors that are required for differentiation of brown adipose tissue (BAT). Experiments are proposed to understand the mechanisms by which expression of Tyk2 regulates BAT differentiation and prevents the development of obesity.