Metabolism in mammals is regulated by complex interplay among different organs. Fatty acid synthesis is increased in white adipose tissue (WAT) when it is inhibited in the liver. Here we identify glycoprotein non-metastatic melanoma protein B (Gpnmb) as one liver–WAT cross-talk factor involved in lipogenesis. Inhibition of the hepatic sterol regulatory element-binding protein pathway leads to increased transcription of Gpnmb and promotes processing of the membrane protein to a secreted form. Gpnmb stimulates lipogenesis in WAT and exacerbates diet-induced obesity and insulin resistance. In humans, Gpnmb is tightly associated with body mass index and is a strong risk factor for obesity. Gpnmb inhibition by a neutralizing antibody or liver-specific knockdown improves metabolic parameters, including weight gain reduction and increased insulin sensitivity, probably by promoting the beiging of WAT. These results suggest that Gpnmb is a liver-secreted factor regulating lipogenesis in WAT, and that Gpnmb inhibition may provide a therapeutic strategy in obesity and diabetes.

哺乳动物中的代谢受到不同器官之间复杂相互作用的调节。当在肝脏中被抑制时，白色脂肪组织（WAT）中的脂肪酸合成会增加。在这里，我们确定糖蛋白非转移性黑色素瘤蛋白B（Gpnmb）是参与脂肪形成的一种肝-WAT串扰因子。肝固醇调节元件结合蛋白途径的抑制导致Gpnmb的转录增加，并促进膜蛋白加工成分泌形式。Gpnmb刺激WAT中的脂肪生成，并加剧饮食引起的肥胖症和胰岛素抵抗。在人体中，Gpnmb与体重指数紧密相关，是肥胖的重要危险因素。中和抗体对Gpnmb的抑制作用或肝脏特异性的抑制作用可改善代谢参数，包括减轻体重增加和增加胰岛素敏感性，这可能是通过促进WAT的解决。这些结果表明，Gpnmb是调节WAT脂肪形成的肝脏分泌因子，而Gpnmb抑制作用可能为肥胖和糖尿病提供治疗策略。