Insulin injection restored increased insulin receptor substrate (IRS)-2 protein during short-term protein restriction but did not affect reduced insulin-like growth factor (IGF)-I mRNA or increased triglyceride accumulation in the liver of rats

Abstract

Dietary protein restriction reduces insulin-like growth factor (IGF)-I synthesis and impairs growth. Moreover, insulin secretion is impaired and hepatic insulin signaling is activated presumably through upregulation of insulin receptor substrate (IRS)-2, which can stimulate lipogenesis thereby resulting in steatosis. In order to determine whether impaired insulin secretion is the primary cause of these changes, we injected insulin into protein-restricted rats and compensated for the reduction in insulin secretion for 1 and 7 d. Insulin infusion did not overcome the reduction in liver IGF-I mRNA nor the hepatic triglyceride accumulation. In contrast, it clearly suppressed the upregulation of hepatic IRS-2 on day 1, but not on day 7. Furthermore, insulin elimination increased IRS-2 in H4IIE-C3 cells. In summary, we found that reduced insulin secretion during protein restriction directly increased hepatic IRS-2 as a rapid response on day 1, while additional mechanisms contributed to the upregulation of IRS-2 on day 7.

Tissue-specific effects of protein malnutrition on insulin signaling pathway and lipid accumulation in growing rats

“…We reported that protein deprivation increases IRS-2 protein levels in the liver; however it affects serine phosphorylation of IRS-1 in the muscle, which is shown to modulate insulin-dependent tyrosine phosphorylation of IRS-1 [6], indicating that each tissue possesses different mechanisms to modulate insulin signaling. We also found that the decrease in plasma insulin levels mediates that protein malnutrition increases IRS-2 protein levels in the liver [38]. Furthermore, amino acid deprivation may directly affect IRS-2 protein levels in cultured hepatocytes (manuscript in preparation).…”

40 YEARS OF IGF1: IGF1 receptor signaling pathways

“…Such a phenotype is typically observed in kwashiorkor, a form of severe protein malnutrition in infants and children. Detailed analysis in this animal model revealed that insulin sensitivity was enhanced in liver and muscle accompanied by a decrease in plasma insulin level (Toyoshima et al 2010, Ozaki et al 2014. In contrast, IGF1 signaling should be suppressed because growth was retarded in these animals.…”

Study of Effects of Blood Amino Acid and Hormone Level for Controlling Triglyceride Accumulation in the Liver of Rats Using Self-Organizing Map

“…We have already reported that protein malnutrition enhances insulin signaling in rat liver followed by accumulation of hepatic lipid [6,7]. In addition, Aoyama et al have reported that triacylglycerol was accumulated in rat liver fed with low-arginine diet [5].…”

“…In the field of nutrition, we and other groups previously reported that dietary protein-malnutrition or protein-restriction caused growth retardation accompanied by hepatic triglyceride (TG) accumulation which was considered to be a kind of NAFLD [4][5][6][7]. It is well established that growth retardation is caused at least in part by the reduction of plasma insulin-like growth factor-I (IGF-I) level and actually it was reduced in animals fed a diet with protein-malnutrition or -restriction [4,8].…”

“…However, the mechanisms underlying the hepatic TG accumulation remains to be elucidated. Given that TG accumulation in the liver can be observed only within a few days after the beginning of dietary protein restriction [7] and the liver is the first organ directly detecting the dietary amino acids absorbed in the gut, we hypothesized that the blood amino acid concentration would play important roles in hepatic TG accumulate.…”