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

Our previous studies have revealed that protein malnutrition enhances insulin signaling in rat liver and muscle in response to a bolus insulin injection. However, it has not been established whether protein malnutrition up-regulates insulin signaling under physiological conditions, such as feeding. Here, we studied the effects of protein malnutrition on insulin signaling after feeding in rat liver, muscle and white adipose tissue (WAT). Six-week-old rats were fed a 15% casein diet (15C) or a calorie-matched 5% casein diet (5C) for 8 h/day during 14 days. On the 15th day, blood and tissues were collected at various time points after feeding. Feeding-induced insulin secretion was reduced in 5C-fed rats compared to 15C-fed rats. The 5C-feeding suppressed immediate activation of insulin receptor after feeding in the liver, muscle, and WAT. However, 5C-feeding constantly increased tyrosine phosphorylation of insulin receptor substrate (IRS)-2 and threonine phosphorylation of eukaryotic initiation factor 4E-binding protein 1 (4E-BP1) in the liver during the examined periods, corresponding to the changes of their amounts. In skeletal muscle, 5C-feeding did not appreciably alter insulin signaling. In WAT, 5C-feeding decreased tyrosine phosphorylation of IRS-1 compared to 15C-feeding. Furthermore, hepatic triglyceride content was increased and feeding-induced acetyl-CoA carboxylase 1 gene expression was enhanced in 5C-fed rats. The 5C-feeding decreased insulin-dependent glucose uptake in adipocytes. These results suggest that enhanced insulin signaling through increased IRS-2 and 4E-BP1 levels in the liver and repressed insulin signaling through decreased IRS-1 levels in WAT contribute to the preferential hepatic lipid accumulation under protein malnutrition.