Jingren Xu1, Canjun Zhu1, Mengyuan Zhang1, Qingchun Tong2, Xiaojuan Wan1, Zhengrui Liao1, Xingcai Cai1, Yaqiong Xu1, Yexian Yuan1, Lina Wang1, Xiaotong Zhu1, Songbo Wang1, Ping Gao1, Qianyun Xi3, Yong Xu4, Qingyan Jiang5, Gang Shu6. 1. Guangdong Province Key Laboratory of Animal Nutritional Regulation, 483 Wushan Road, Tianhe District, Guangzhou, Guangdong 510642, China. 2. Brown Foundation Institute of Molecular Medicine, The University of Texas Health Science Center at Houston, 7000 Fannin, Suite 1800, Houston, TX 77030, USA. 3. Guangdong Province Key Laboratory of Animal Nutritional Regulation, 483 Wushan Road, Tianhe District, Guangzhou, Guangdong 510642, China; National Engineering Research Center for Breeding Swine Industry, College of Animal Science, South China Agricultural University, 483 Wushan Road, Tianhe District, Guangzhou, Guangdong 510642, China. 4. Department of Molecular and Cellular Biology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA. 5. Guangdong Province Key Laboratory of Animal Nutritional Regulation, 483 Wushan Road, Tianhe District, Guangzhou, Guangdong 510642, China; National Engineering Research Center for Breeding Swine Industry, College of Animal Science, South China Agricultural University, 483 Wushan Road, Tianhe District, Guangzhou, Guangdong 510642, China. Electronic address: qyjiang@scau.edu.cn. 6. Guangdong Province Key Laboratory of Animal Nutritional Regulation, 483 Wushan Road, Tianhe District, Guangzhou, Guangdong 510642, China; National Engineering Research Center for Breeding Swine Industry, College of Animal Science, South China Agricultural University, 483 Wushan Road, Tianhe District, Guangzhou, Guangdong 510642, China. Electronic address: shugang@scau.edu.cn.
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.
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.