The Effects Of Neonatal Glucocorticoids Treatment On The Blood Glucose Levels And Energy Metabolism In Adult Rats

Objective: Glucocorticoids(GCs)have been widely used to treat chronic lung disease due to its anti-inflammatory and immunosuppressive effects.However,more and more experiments show that early treatment of glucocorticoid may cause long-term negative effects,including hypertension,alteration in social behavior,permanent changes in the function of the thalamus-pituitary-adrenal axis,and even reduced lifespan.Studies have suggested that,some early life factors may predispose increased risk of metabolic disease in adult life.However,the effects of neonatal dexamethasone administration on the blood glucose levels and energy metabolism in adult have been little investigated.Liver performs important role in many metabolic processes,hepatic dysfunction may correlated with pathogenesis of metabolic diseases.Peroxisome proliferator-activated receptor gamma coactivator-1 alpha(PGC-1?)and Adenosine 5'-monophosphate activated protein kinase(AMPK)are the key enzymes in the liver and involved in the energy metabolism.In the present study,we aim to investigate the effect of neonatal glucocorticoids treatment on blood glucose,energy metabolism and hepatic gene expression in adult.Methods: Newborn Wistar male pups were randomly divided into DEX and SAL groups on the day of birth(Day 0).Rats were injected with DEX and control animals were injected with saline(SAL)respectively at 1–3 days.At24 weeks of age,the body weight was measured.Automated metabolic ages(CLAMS)were used to check energy metabolism by detecting the oxygen consumption,carbon dioxide production,physical activity,as well as food and water consumption.The oral glucose tolerance(OGTT)were performed.Animals were fasted for 12 hours and then fed with 50% glucose solution(2g /kg),and blood samples were collected at 0min,30 min,60min,120 min and180min time points.Blood glucose and insulin levels were all measured.Rats were sacrificed and liver tissue were collected.Proteins were extracted from liver tissues and Western Blot was used to detect gene expressions of PGC-1?,AMPK and p-AMPK.Results:1 Compared with SAL-treated rats,neonatal DEX administration caused no differences in body weight(g),liver weight(g)and liver/body weight(%)ratio at 24 weeks(Body weight: DEX vs.SAL: 372.88 ± 3.55 vs.365.02±41.99,P>0.05;liver weight: DEX vs.SAL: 10.31±0.51 vs.9.71±1.14,P>0.05;liver/body weight: DEX vs.SAL: 2.78±0.24 vs.2.66±0.05,P>0.05).2 Data from energy metabolic cages indicated that there were no significant differences found in the Oxygen consumption(VO2),heat production(Heat),food consumption(VDM Acc)and water consumption(Feed Acc)at 24 weeks between SAL and DEX groups.However,DEX treatment caused significantly reduced CO2 production(VCO2)and respiration rate(RER)when compared with SAL-treated rats,indicating neonatal DEX administration may lead to altered energy substrate utilization in 24 wks old rats.3 The results of OGTT have indicated that,neonatal DEX administration may led to significantly increased blood glucose level at 180 min time point when compared with SAL controls(DEX vs.SAL: 7.92±0.52 vs.6.04±1.29,P<0.05).Compared with SAL rats,neonatal DEX administration caused no differences in insulin levels.4 Compared with SAL-treated animals,neonatal DEX treatment caused no alteration in hepatic AMPK expression at protein level at 24 wks of age.However,significantly reduced hepatic PGC-1? expression and pAMPK/AMPK ratio were all found in DEX group when compared with agematched controls.Conclusions:1 No statistical differences were found in body weight,liver weight andliver/body ratio between SAL and DEX-treated animals at 24 weeks of age.Indicating that neonatal DEX administration could not cause permenate alterations in body and liver weight.2 Neonatal DEX administration may lead to significant reduced of VCO2 and RER,indicating there might be alterations in body energy utilization.3 Neonatal DEX administration caused postponed peak of blood glucose levels during OGTT,indicating there might be disturbed glucose metabolism.Insulin levels of OGTT in 24 weeks old rats.Where were no differences found between two groups at all time points.The effect of neonatal dexamethasone administration on the blood insulin levels in adult was further validated.4 AMPK,PGC-1? are the key enzymes in the liver involved in the energy metabolism.Neonatal DEX administration led to decreased hepatic gene expressions of PGC-1? and ratio of p-AMPK/AMPK at 24 weeks old rats,indicating altered there may exist glucose and lipid metabolism in the liver.