Post-weaning HFD Exacerbates Maternal HFD Induced Blood Pressure Response And Metabolic Dysfunction In Both Male And Female Offspring

Obesity is a growing global health crisis,and a large number of animal and human studies have demonstrated that maternal obesity and high fat diet(HFD)are associated with cardiovascular diseases such as heart failure and hypertension.Offspring from obese mother or mother with HFD during pregnancy have elevated basal blood pressure in childhood or adolescence,putting them at increased risk for the development of hypertension in adulthood.Animal experiments revealed that prenatal adverse factors,including gestational hypertension,uterine placental insufficiency and protein restriction lead to offspring hypertension.Either elevated sympathetic nervous system activity,excessive activation of the renin-angiotensin-aldosterone system(RAAS)or pro-inflammatory cytokines(PICs)have been identified as contributing factors for hypertension programming.However,effects of maternal obesity or HFD on offspring central nervous system(CNS)leading to development of hypertension has not been fully elucidated,especially the CNS mechanism underlying this process.The present study from our laboratory mainly investigated whether the high-fat diet after weaning can aggravate the metabolic syndrome and programmed hypertension sensitized by maternal HFD,and whether there are sex differences in these metabolic and cardiovascular dysfunctions.Furthermore,we determined the central mechanisms underlying this process,which involves alteration of brain renin-angiotensin system(RAS),oxidative stress and inflammatory cytokines in the offspring.To do so,female mothers were fed with high-fat Diet(HFD)or normal Diet(CD)at 1 week before pregnancy and during pregnancy and lactation.After weaning,offspring were continuously fed with HFD.The offspring fed with CD were set as controls.This yielded three groups,1)Offspring from CD dams were fed CD(OCC),2)offspring from CD dams were fed HFD(OCH),3)offspring from HFD dams were fed HFD(OHH).Each group included 5-6 animals and they were fed CD or HFD until the age of 12 weeks.At the age of 11 weeks,femoral arteriovenous catheterization was performed on male and female offspring.At the age of 12 weeks,nitroprusside and phenylephrine were pumped into the femoral arteriovenous vein to observe changes in blood pressure and heart rate,so as to evaluate baroreflex sensitivity(BRS)under conscious state.In separate groups,11 weeks old male and female offspring were implanted with femoral artery catheter and lateral ventricle cannula.After one week recovery,either ANG II or TNF-α was microinjected into the lateral ventricle to observe blood pressure responses so that whether post-weaning HFD enhanced brain sensitivity to ANG II and TNF alpha in the offspring.mRNA expression of RAS components,NADPH oxidase and proinflammatory cytokines in LT and PVN regions were also determined to further assess the mechanisms underlying post-weaning HFD-induced dysfunction in metabolism and blood pressure responses in both sex offspring from HFD dams.Our results showed that post-weaning HFD in the male offspring from HFD dams resulted in significant increases in the body weight,feed efficiency,daily energy intake and baseline blood pressure.Whether exposed to HFD during pregnancy and lactation or not,post-weaning HFD in male offspring led to the baroreflex dysfunction and increased the blood pressure response to ICV acute administration of either ANG II or TNF-.Likewise,in female offspring,post-wearing HFD also significantly increased body weight,basal blood pressure and caused baroreflex dysfunction when compared with OCC.In comparison to the male offspring,post-weaning HFD did not affect the feed efficiency and daily energy intake of the female offspring and their blood pressure response to icv ANG II and TNF-α.Moreover,male offspring exposed to HFD after weaning exhibited upregulated mRNA expressions of RAS component and pro-inflammatory factors in the structures of LT and PVN,while the mRNA expressions of RAS component and NADPH oxidase in LT and PVN of female offspring were not upregulated.Our data indicate that,no matter whether HFD exposed to pregnancy and lactation,post-weaning HFD affects baroreceptor reflex function in the offspring,and results in a sex specific mRNA expression of brain RAS components and proinflammatory factors.Notably,post-weaning HFD enhances blood pressure response to ICV injection of either ANG II or TNF alpha in male offspring,but not in female offspring,suggesting that male offspring from HFD dams are susceptibility to develop hypertension,which is further exacerbated by the occurrence of obesity(post-weaning HFD).This study also revealed the sex differences in the effects of maternal HFD during pregnancy and lactation on metabolism,blood pressure and brain nuclei involved in cardiovascular regulation.Our study provides new evidence for how maternal HFD and post-weaning HFD affects metabolic and cardiovascular functions in the male and female offspring,and represents a new therapeutic strategy for intervention of the development of hypertension or obesity in the future.