| Objective: To investigate the influence of chronic intrauterine hypoxia(CIH) on glycolipid metabolism in offspring male rats; preliminary study the metabolism reprogramming induced by different juvenile activity and its molecular mechanism.Methods: Twenty pregnant Sprague-Dawley rats were randomly divided into CIH group and normal controls. Hypoxia intervention in the middle and late pregnancy was performed. Differentially expressed genes(DEGs) in skeletal muscle of neonatal males were screened and bioinformatics analyzed by digital gene expression profiles. Physical characteristics, blood-borne biomarkers were examined in neonates and adults. And the expression of glycolipid metabolism related proteins were tested by Real-time PCR and Western Blot assay. Male offspring of 5-week-old were respectively assigned to different juvenile activity subgroup(sedentariness, cage activity and exercise) for 13 weeks intervention. After general data collection and intraperitoneal injection of glucose tolerance test, specimens were gathered. Blood-borne factors and intramuscular oxidative / antioxidant balance were detected by colorimetric method and radioimmunoassay; pathological slice was observed and immunohistochemically analyzed; main proteins were evaluated by Western blot assay.Results: 1. CIH programmed to 396 DEGs in skeletal muscle of offspring male neonates including 287 upregulated and 109 downregulated(P<0.05). DEGs were significantly enriched in glycolipid metabolism, insulin and peroxisome proliferator-activated receptorsignaling pathway by functional annotation. 2. In offspring male neonates, CIH programmed to low birth weight, catch-up growth andhyperlipidemia. At molecular level, the m RNA and protein expression of phosphoenolpyruvate carboxykinase(PEPCK), fatty acid synthase(FASN) and stearoyl-Co A desaturase 1(SCD-1) were significantly enhanced(P<0.05), insulin signaling pathway were up-regulated(P<0.05), while fatty acid oxidase carnitine palmitoyltransferase 1?(CPT-1?) and mitochondria uncoupling protein 2 were inhibited(P<0.05). In offspring adults, hyperlipemia and insulin resistance were detected with enhanced PEPCK, FASN, SCD-1 and CPT-1? m RNA and protein expression(P<0.05), while insulin signaling pathway were downregulated(P<0.05). 3. Juvenile sedentariness exacerbated elevated fat content, postprandial(15min, 30 min, 60min) hyperglycaemia(P<0.05) and peripheral insulin resistance(Lg HOMA-IR, 1.02 ± 0.1 vs. 0.83 ± 0.0, P<0.05). However, muscular oxidative / antioxidant levels were unchanged(P>0.05). Under the light microscope, the morphology and structure of skeletal muscle were unchanged after CIH and different juvenile activity. Under the electron microscope, large scattered lipid droplets were seen in juvenile sedentariness; disorder muscle fibers and an increase in the number of mitochondria were seen in juvenile exercise group. Compared with normal controls, insulin-stimulated glucose transporter m-GLUT4/t-GLUT4 did not change correspondingly to p-Akt/Akt(P>0.05) in juvenile sedentariness. Additionally the expression of fatty acid binding protein 3, CPT-1 were downregulated and FASN were significantly upregulated(P<0.05). Above metabolic disorders phenotype could partly normalized by juvenile exercise. Elevated serum interleukin 6 concentration(152.4 ± 20.4 ng/L vs. 123.2 ± 26.9 ng/L, P<0.05), enhanced skeletal muscular citrate synthase activity and significantly upregulated insulin-stimulated m-GLUT4/t-GLUT4 were detected in juvenile exercise(P<0.05).Conclusions: CIH programmed to DEGs in skeletal muscle of offspring male neonates, especially enriched in glycolipid metabolism. Programming of enhanced gluconeogenesis and lipid synthesis from neonates to adults might be the possible mechanism of CIH related chronic metabolic disease. CIH induced metabolic adaption could be reprogrammed by different juvenile activity. Changes in the intramuscular glucose up-take and lipid metabolism were potentially responsible for the metabolic reprogramming. |
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