Arginine reverses growth hormone resistance through the inhibition of toll-like receptor 4-mediated inflammatory pathway.

ABSTRACT

OBJECTIVE: Growth hormone stimulates growth by increasing insulin-like growth factor 1 expression and secretion. In the presence of insufficient nutrients, GH increases, whereas IGF-1 expression becomes severely suppressed, leading to GH resistance. This study aimed to explore the effect of arginine (Arg) on GH resistance during malnutrition and to describe its underlying mechanism. METHODS: C57BL/6J mice were injected intraperitoneally with Arg for 1h or subjected to caloric restriction with Arg supplement in drinking water for 18days. HepG2 cells were exposed to different Arg concentrations for 24h. Signaling pathway agonists/inhibitors, siRNA, and overexpression plasmids were used to investigate the underlying molecular mechanism. Liver-specific toll-like receptor (TLR4) knockout mice were utilized to clarify the role of TLR4 in Arg-induced IGF-I expression and secretion. RESULTS: Arg inhibited the TLR4 downstream pathway by binding to TLR4 and consequently activated Janus kinase 2/signal transducer and activator of transcription 5 signaling pathway. As a result, IGF-1 transcription and secretion increased. Arg activity was absent in liver-specific TLR4 knockout mice and was greatly suppressed in liver with overexpressed TLR4, suggesting that hepatic TLR4 was required and sufficient to induce GH resistance. By contrast, the mammalian target of rapamycin pathway was unnecessary for Arg activity. Arg not only significantly increased IGF-1 expression and secretion under acute fasting and chronic CR conditions but also attenuated body weight loss. CONCLUSIONS: Our results demonstrate a previously unappreciated pathway involving Arg that reverses GH resistance and alleviates malnutrition-induced growth restriction through the inhibition of TLR4-mediated inflammatory pathway.