GPNMB

Metabolism in mammals is regulated by the complex interplay between different organs, and fatty acid synthesis is a key process that is modulated differently in white adipose tissue (WAT) and the liver. In this study, we identify glycoprotein non-metastatic melanoma protein B (Gpnmb) as a critical factor involved in liver-WAT cross-talk and lipogenesis regulation. We show that inhibition of the hepatic sterol regulatory element-binding protein (SREBP) pathway leads to increased transcription of Gpnmb and promotes its processing into a secreted form. Gpnmb acts to stimulate lipogenesis in WAT, exacerbating diet-induced obesity and insulin resistance. Human data also reveal that Gpnmb is tightly associated with body mass index and serves as a strong risk factor for obesity. Importantly, inhibiting Gpnmb using a neutralizing antibody or through liver-specific knockdown improves metabolic parameters, including reduced weight gain and enhanced insulin sensitivity, likely through promoting the beiging of WAT. These findings highlight Gpnmb as a liver-secreted factor that regulates lipogenesis in WAT and suggest that targeting Gpnmb could offer a potential therapeutic strategy for managing obesity and diabetes.