Prenatal High-salt Diet Induced Glucose Metabolism Disorder In Adult Male Rat Offspring And Its Underlying Mechanisms

Background:The World Health Organization currently recommends that salt intake of 5 grams per day,while most populations exceed this recommendation.According to the investigation of "Guidelines of diets for chinese residents",daily salt intake for local chinese is 10.5g.Notably,women may increase salt consumption due to physiological and taste changes in pregrancy.Numerous evidences have revealed a robust relationship between high-salt intake and insulin resistance in human and animal adults.Prenatal high-salt(HS)diet has been shown to impair the offspring’s cardiovascular systems.However,little is known regarding the effects of gestational HS diet on the offspring’s glucose metabolism.Therefore,the objectives of this study are to determine the influence and mechanisms of prenatal HS diet on the offspring’s metabolism,offering new information on metabolic diseases in fetal origins and for early prevention.Methods:Pregnant SD rats are fed either a normal-salt(1%NaCl)or high-salt(8%NaCl)diet during the whole pregnancy.Experiments are conducted in five-month-old male offspring.We used HE staining to evaluate the pathological changes of skeletal muscle,used transmission electron microscopy to observe the mitochondrial ultrastructure.Gene expression in the skeletal muscle was determined by Western-blot and qRT-PCR analysis.The offspring(N=20)were randomly selected from different litters of HS group for exercise training.After exercise training,glucose and insulin tolerance tests and qRT-PCR analysis were performed.Results:The present study shows the following findings:1)chronic maternal exposure to HS diet during pregnancy decreased glucose tolerance and insulin sensitivity in the five-month-old male offspring;2)the expression of peroxisome proliferator activated receptor gamma coactivator 1α(PGC-1α)was reduced,which led to decreased mitochondrial biogenesis and respiration in the skeletal muscle;3)the down-regulation of PGC-1α was accompanied by the decreased expression of glucose transporter type 4(GLUT4);4)DNA hyper-methylation of PGC-1α was increased;5)in HS offspring,endurance exercise training increased levels of PGC-1α and its downstream genes,which ultimately reversed the metabolic dysfunction.Conclusion:These findings suggest that maternal HS diet during gestation markedly downregulated the expression of PGC-1α via DNA hyper-methylation in the skeletal muscle of adult offspring,which led to impaired mitochondrial functions and reduced GLUT4 levels,eventually leading metabolic disorders.Exercise training in HS offspring reversed the metabolic dysfunction by increasing the level of PGC-1α.