We previously examined the association between ectopic fat and organ-specific insulin resistance in insulin-target organs in patients with nonalcoholic fatty liver disease (PLOS ONE 2014). Unexpectedly, fat accumulation in the skeletal muscle and adipose tissue was not associated with organ-specific insulin resistance. Instead, liver fat was associated not only with hepatic insulin resistance, but also with skeletal muscle insulin resistance, supporting a central role of fatty liver in systemic insulin resistance. The findings also suggest a network exists between the liver and skeletal muscle, 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. Hepatic expression of LECT2 was upregulated on high fat diet feeding and physical inactivity in mice. 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 fatty liver-associated skeletal muscle insulin resistance, and suggest that LECT2 may be a therapeutic target for obesity-associated insulin resistance.