Chronic Parenteral Nutrition Induces Hepatic Inflammation, Steatosis, and Insulin Resistance in Neonatal Pigs1–3

Abstract

Prematurity and overfeeding in infants are associated with insulin resistance in childhood and may increase the risk of adult disease. Total parenteral nutrition (TPN) is a major source of infant nutritional support and may influence neonatal metabolic function. Our aim was to test the hypothesis that TPN induces increased adiposity and insulin resistance compared with enteral nutrition (EN) in neonatal pigs. Neonatal pigs were either fed enteral formula orally or i.v. administered a TPN mixture for 17 d; macronutrient intake was similar in both groups. During the 17-d period, we measured body composition by dual-energy X-ray absorptiometry scanning; fasting i.v. glucose tolerance tests (IVGTT) and hyperinsulinemic-euglycemic clamps (CLAMP) were performed to quantify insulin resistance. On d 17, tissue was collected after 1-h, low-dose CLAMP for tissue insulin signaling assays. TPN pigs gained less lean and more body fat and developed hepatic steatosis compared with EN pigs. After 7 and 13 d, IVGTT showed evidence of insulin resistance in the TPN compared with the EN group. Fasting plasma glucose and insulin also were higher in TPN pigs. CLAMP showed that insulin sensitivity was markedly lower in TPN pigs than in EN pigs. TPN also reduced the abundance of the insulin receptor, insulin receptor substrate 1, and phosphatidylinositol 3 kinase in skeletal muscle and liver and the proliferation of total pancreatic cells and β-cells. Hepatic proinflammatory genes as well as c-Jun-N-terminal kinase 1 phosphorylation, plasma interleukin 6, and tumor necrosis factor-α were all higher in TPN pigs than in EN pigs. The results demonstrate that chronic TPN induces a hepatic inflammatory response that is associated with significant insulin resistance, hepatic steatosis, and fat deposition compared with EN in neonatal pigs. Further studies are warranted to establish the mechanism of TPN-induced insulin resistance and hepatic metabolic dysfunction and whether there are persistent metabolic consequences of this lifesaving form of infant nutritional support.

Multi-omic profiles of hepatic metabolism in TPN-fed preterm pigs administered new generation lipid emulsions

“…The downstream metabolite of ceramide, sphingosine, did not show any difference in content in the liver either. It would therefore growth, which we reported previously (24). A major concern of PN-fed premature infants is the growth and neurodevelopment of the brain.…”

“…Moreover, the presence of hepatomegaly in all PN groups occurred despite the prevention of steatosis and cholestasis in the OV and SL versus IL piglets (7). Our previous study also showed that TPN-induced hepatomegaly was due to increased protein and DNA, but not lipid content (24). The differential increase in these vital organs among all PN groups, but lower body growth rates in IL versus OV and SL piglets, points to a limitation in lean/skeletal muscle significantly (P < 0.05) decreased in all TPN groups compared with ENT.…”

“…Relative quantification of target mRNA expression was calculated and normalized to GAPDH or actin expression. All reactions were performed under the following thermal cycling conditions: 10 min at 95°C followed by 40 cycles of 95°C for 15 s and 60°C for 60 s. The 2 CT method was used to compare gene formula (Litter Life; Merrick, Middletown, WI) at 240 ml/kg in eight feeds per day (24). Postsurgery, TPN was started at 5 ml/(kg·h) and gradually increased to 10 ml/(kg·h).…”

“…Samples were flash-frozen in liquid nitrogen and stored at 80°C until analysis. Glucose and insulin were analyzed as previously described (24). As piglets were on continuous TPN infusion, they received a constant glucose infusion rate.…”

Impact of New-Generation Parenteral Lipid Emulsions in Pediatric Nutrition

“…Although many components of TPN have been implicated in both animal and human studies of PNALD, recent interest has focused on the lipid component of TPN as being a major factor in the development of cholestasis (2). In the United States, only one form of lipid is fully approved for use in infants and children.…”