Hepatokine ERAP1 Disturbs Skeletal Muscle Insulin Sensitivity via Inhibiting USP33-Mediated ADRB2 Deubiquitination

Chronic inflammation in liver induces insulin resistance systemically and in other tissues, including the skeletal muscle (SM); however, the underlying mechanisms remain largely unknown. By performing RNA-seq of primary hepatocytes from wild-type mice fed long term high-fat diet (HFD), which have severe chronic inflammation and insulin resistance, we found that the expression of hepatokine endoplasmic reticulum aminopeptidase 1 (ERAP1) was upregulated by HFD. Increased ERAP1 levels were also observed in interferon-γ-treated primary hepatocytes. Furthermore, hepatic ERAP1 overexpression attenuated systemic and SM insulin sensitivity, whereas hepatic ERAP1 knockdown had the opposite effects, with corresponding changes in serum ERAP1 levels. Mechanistically, ERAP1 functions as an antagonist-like factor, which interacts with β2 adrenergic receptor (ADRB2) and reduces its expression by decreasing ubiquitin specific peptidase 33 (USP33)-mediated deubiquitination, and thereby interrupts ADRB2-stimulated insulin signaling in the SM. Taken together, ERAP1 is an inflammation-induced hepatokine that impairs SM insulin sensitivity. Its inhibition may provide a therapeutic strategy for insulin resistance-related diseases, such as type 2 diabetes.