LECT2 functions as a hepatokine that links obesity to skeletal muscle insulin resistance

Recent papers have reported an association between fatty liver disease and systemic insulin resistance in humans, but the causal relationship remains unclear. The liver may contribute to muscle insulin resistance by releasing secretory proteins, termed hepatokines. Here, we demonstrate that leukocyte cell-derived chemotaxin 2 (LECT2), as an energy-sensing hepatokine, is a link between obesity and skeletal muscle insulin resistance. Circulating LECT2 positively correlated with the severity of both obesity and insulin resistance in humans. LECT2 expression was negatively regulated by starvation-sensing kinase adenosine monophosphate-activated protein kinase (AMPK) in H4IIEC hepatocytes. Genetic deletion of LECT2 in mice increased insulin sensitivity in the skeletal muscle. Treatment with recombinant LECT2 protein impaired insulin signaling via phosphorylation of JNK in C2C12 myocytes. These results demonstrate the involvement of LECT2 in glucose metabolism, and suggest that LECT2 may be a therapeutic target for obesity-associated insulin resistance.