Neonatal overfeeding induced glucocorticoid overexposure accelerates hepatic lipogenesis in male rats

Postnatal overfeeding activates tissue glucocorticoid (GC) activity by up-regulating 11β-hydroxysteroid dehydrogenase 1 (11β-HSD1) and increasing sensitivity to high-fat (HF) diet-induced non-alcoholic fatty liver disease (NAFLD). The present study aimed to evaluate the effects of postnatal overfeeding on GC regulation and lipogenesis in the liver and to observe the impact of GC on hepatocyte lipid metabolism.

In vivo, Male Sprague-Dawley rat pup litters were adjusted to litter sizes of three (small litter, SL) or ten (normal litter, NL) on postnatal day 3 and then given standard chow from postnatal week 3 (W3) to W13. In vitro, HepG2 cells were stimulated by GC, mifepristone (Mi) or GC + Mi within 48 h, followed by sodium oleate (OA) intervention (or not) for 24 h. Intracellular lipid droplets, triglyceride (TG) concentrations and gene expression related to lipid metabolism were measured in hepatic tissues or HepG2 cells.

In vivo, weight gain in the body and liver and TG concentrations in the liver were significantly increased in the SL rats compared to the NL rats at W3 and W13 (p < 0.05); mRNA expression of hepatic 11β-HSD1, acetyl-CoA carboxylase 1 (ACC), stearoyl-CoA desaturase-1 (SCD1), fatty acid synthase (FASN) and their nuclear transcription factor, sterol regulatory element binding protein-1c (SREBP-1c) (p < 0.05), was also increased. In vitro, intracellular lipid droplets and TG content in HepG2 cells increased under stimulation with GC or OA (p < 0.05); the increase was more significant following treatment with GC and OA together (p < 0.05). The ACC, SCD1, FASN and SREBP-1c mRNA expression changes were highly similar to the changes in TG content in cells. All the changes induced by GC disappeared when the glucocorticoid receptor (GR) was blocked by Mi.

Postnatal overfeeding induced GC overexposure through 11β-HSD1 up-regulation in the liver. GC activated hepatic de novo lipogenesis (DNL) via GR and led to hepatic lipid accumulation, which increased the risk of NAFLD during adulthood.