Effects Of Maternal High Fat Diet On Development And Metabolic Disorder Of Offspring

ObjectiveKeeping diet balance during pregnancy is essential for early fetal development,postnatal development and long-term health.Maternal obesity and high fat diet during pregnancy are the key factors affecting the growth and the incidence of chronic metabolic diseases in the adulthood of offspring,which has become one of the major health issues of current society.This study revealed the effects of high-fat diet during pregnancy on offspring's growth,glucose and lipid metabolism from the aspects of clinical epidemiology and concerned hypothalamic central regulation by utilizing a mice model.Methods1.Retrospective and prospective cohort study were used to analyze 1 the associations between pre-pregnancy BMI,early pregnancy blood lipids,blood glucose levels and perinatal outcomes.A questionnaire-based diet evaluation during pregnancy were conducted in a prospective cohort to estimate the association maternal nutritional status and adverse pregnancy outcomes.2.we established a maternal high-fat diet mice model,and follow up the offspring's growth,and the long-term effect of glucose and lipids metabolism of the offspring.Confocal microscopy and immunoblotting were used to detect the number and the expression of proopiomelanocortin(POMC)neurons,which functioned as inhibiting food intake and promoting energy metabolism.3.Embryonic(E16.5)hypothalamic neural stem cells(htNSCs)were used as an in vitro cell model to study the effects of amylin and its receptors on the formation of POMC neurons.RNA pulldown was conducted to explore the candidate protein,which specifically bind to Ramp3 in htNSCs and maintains its mRNA stabilityResults1.It is shown that pre-pregnancy BMI were significantly associated with the obstetric complications such as gestational hypertension,gestational diabetes mellitus,and premature delivery,as well as the adverse neonatal outcomes such as macrosomia and large for gestational age.For women with normal weight,or overweight and obese,elevated lipids and glucose levels would aggravate the risk of adverse outcomes mentioned above.Furthermore,we found that maternal high fat diet,especially in the 2nd trimester,could not only increase the risk of large for gestational age,but also increase the risk of gestational hypertension,gestational diabetes mellitus and preterm birth.2.We found that maternal high fat diet during pregnancy could lead to higher risk of impaired glucose tolerance,insulin resistance and hyperlipidemia in male offspring.By confocal microscopy and immunoblotting,we found that the number and the expression of POMC neurons were decreased in the adult male offspring of high-fat diet group.On the meanwhile,we also detected an increased level of amylin from the embryonic E16.5 days and lasted to adulthood,which is closely related to the formation of hypothalamic POMC neurons.3.The results showed that the decrease of Ramp3 expression in htNSCs in the high fat diet group during pregnancy inhibited the Stat3 and Erk signaling pathway,which is the downstream of amylin receptor.Using shRNA knockdown and in vitro differentiation of htNCSs,we found that decreased Ramp3 expression in htNSCs could inhibit the promotion effect of amylin on the POMC neurons differentiation.It was found that the mRNA binding protein IGF2BP1 could specifically bind to Ramp3 in htNSCs and maintains its mRNA stability by using RNA pulldown.Importantly,the IGF2BP1 expression in htNSCs in the high fat diet group is decreased,which could decrease Ramp3 expression,and further lead to an inhibition the POMC neurons differentiation and then result in adult obesity and metabolic disorders.ConclusionMaternal obesity and over nutrition is associated with negative perinatal outcomes including preterm birth and LGA.High-fat diet during pregnancy can down-regulate IGF2BP1 in the fetal mice's hypothalamus,then reduce the binding to Ramp3 mRNA and decrease its stability,resulting in impaired ability of hypothalamic neural stem cells to differentiate POMC neurons,eventually change their feeding behavior and metabolic function.It is one of the key mechanism underlie the increased birth weight and glucose and lipid metabolism disorder in adulthood in male offspring induced by maternal high fat diet.