Fetuin B is a secreted hepatocyte factor linking steatosis to impaired glucose metabolism

 Liver steatosis is associated with the development of insulin resistance and the pathogenesis of type 2 diabetes. We tested the hypothesis that protein signals originating from steatotic hepatocytes communicate with other cells to modulate metabolic phenotypes. We show that the secreted factors from steatotic hepatocytes induce pro-inflammatory signaling and insulin resistance in cultured cells. Next, we identified 168 hepatokines, of which 32 were differentially secreted in steatotic versus non-steatotic hepatocytes. Targeted analysis showed that fetuin B was increased in humans with liver steatosis and patients with type 2 diabetes. Fetuin B impaired insulin action in myotubes and hepatocytes and caused glucose intolerance in mice. Silencing of fetuin B in obese mice improved glucose tolerance. We conclude that the protein secretory profile of hepatocytes is altered with steatosis and is linked to inflammation and insulin resistance. Therefore, preventing steatosis may limit the development of dysregulated glucose metabolism in settings of overnutrition. Meex et al. use proteomic approaches to identify steatosis as a factor that changes protein secretion in hepatocytes. Secreted factors from steatotic hepatocytes caused insulin resistance and inflammation. One secreted protein, fetuin B, was identified as a hepatokine that is increased in type 2 diabetes and causes impaired glucose metabolism.