Multidrug resistance protein 4 (Mrp4) is an efflux transporter known to transport several xenobiotics and endogenous molecules. We recently identified that the lack of Mrp4 increases adipose tissue and body weights in mice. However, the role of Mrp4 in adipose tissue physiology are unknown. The current study aimed at characterizing these specific roles of Mrp4 using wild-type (WT) and knockout (Mrp4-/- ) mice. Our studies determined that Mrp4 is expressed in mouse adipose tissue and that the lack of Mrp4 expression is associated with adipocyte hypertrophy. Furthermore, the lack of Mrp4 increased blood glucose and leptin levels, and impaired glucose tolerance. Additionally, in 3T3-L1 cells and human pre-adipocytes, pharmacological inhibition of Mrp4 increased adipogenesis and altered expression of adipogenic genes. Lack of Mrp4 activity in both of our in vivo and in vitro models leads to increased activation of adipose tissue cAMP response element-binding protein (Creb) and decreased plasma prostaglandin E (PGE) metabolite levels. These changes in Creb activation, coupled with decreased PGE levels, together promoted the observed metabolic phenotype in Mrp4-/- mice. In conclusion, our results indicate that Mrp4 as a novel genetic factor involved in the pathogenesis of metabolic diseases, such as obesity and diabetes.

中文翻译：

---

多药耐药相关蛋白 4 (Mrp4) 是肥胖和糖尿病发病机制中的新遗传因子

多药耐药蛋白 4 (Mrp4) 是一种外排转运蛋白，已知可转运多种异生物质和内源性分子。我们最近发现，缺乏 Mrp4 会增加小鼠的脂肪组织和体重。然而，Mrp4 在脂肪组织生理学中的作用尚不清楚。目前的研究旨在使用野生型 (WT) 和敲除 (Mrp4-/- ) 小鼠来表征 Mrp4 的这些特定作用。我们的研究确定Mrp4 在小鼠脂肪组织中表达，并且Mrp4 表达的缺乏与脂肪细胞肥大有关。此外，缺乏Mrp4会增加血糖和瘦素水平，并降低葡萄糖耐量。此外，在 3T3-L1 细胞和人类前脂肪细胞中，Mrp4 的药理学抑制增加了脂肪生成并改变了脂肪基因的表达。在我们的体内和体外模型中缺乏 Mrp4 活性导致脂肪组织 cAMP 反应元件结合蛋白 (Creb) 的激活增加和血浆前列腺素 E (PGE) 代谢物水平降低。Creb 激活的这些变化，加上 PGE 水平的降低，共同促进了在 Mrp4-/- 小鼠中观察到的代谢表型。总之，我们的研究结果表明，Mrp4 作为一种新的遗传因子参与了代谢疾病的发病机制，例如肥胖和糖尿病。