The Effects Of Maternal Hypoxia During Pregnancy On Insulin Resistance In Rats Offspring And Its Mechanism

Objective: To explore the effects of maternal hypoxia (MH) during pregnancy on insulinresistance in rat offspring and adipocytokine secreted frizzled-related protein5(Sfrp5) itspossible molecular mechanism contribute to insulin signaling pathway.Mehtods: According to factorial normal oxygen and maternal under hypoxia environment,Sprague-Dawley (SD) rats were randomly divided into two groups as normal oxygen group(control group,21%O2) and maternal hypoxia during pregnancy group (MH group,10%O2).After delivery, two male offspring of each mother rat were taken out and breast-fed for threeweeks. After weaning, according to a2×2factorial design, consisting of two factors[maternal hypoxia (MH) and postnatal high-fat diet (HFD)], each with two levels, maleoffspring were randomly assigned into four groups (each containing12animals) as follows:maternal hypoxia offspring with postnatal high-fat diet [MH+HFD]; maternal hypoxiaoffspring with postnatal normal diet [MH]; maternal normoxia offspring with postnatalhigh-fat diet [HFD]; maternal normoxia offspring with normal diet [Control]. At Week3andWeek15, blood fat, fasting plasma glucose (FPG), serum total cholesterol (TC), triglyceride(TG), free fatty acid (FFA), low-density lipoprotein cholesterin (LDL-C), high-densitylipoprotein cholesterin (HDL-C) were measured by biochemical methods, and insulin wasmeasured by radioimmunoassay, and then the homeostasis model assessment-insulinresistance index (HOMA-IR) was calculated. HOMA-IR was used for insulin resistancemeasurement, the formula for HOMA-IR was: FPG (mmol/L)×FINS (mIU/L)/22.5.Observed The structural changes of rat adipose tissue and liver tissue; determined theprotein expression of a specific marker of activated macrophage (F4/80) in all the treated rats;meanwhile, the expression of Sfrp5, as well as Wnt5a and the molecular mechanismsinvolved in Wnt5a/JNK(P-JNK-1(Thr183/Tyr185), P-c-Jun(Ser63), P-IRS-1(Ser307) andinsulin signaling pathway were measured by Western Blot (WB）and quantitative real-time polymerase chain reaction（QRT-PCR）in Sprague-Dawley rat offspring adipose tissue.Results: Maternal hypoxia caused a relative increased insulin levels and P-IRS-1proteinexpression in offspring compared to the normoxic counterparts(all P<0.05). In addition, asignificantly decreased Sfrp5mRNA and protein concentrations in adipose tissue couple withincreased Wnt5a protein was found in the same maternal hypoxia offspring (all P<0.05); andthose changes were accompanied by increased P-JNK-1(Thr183/Tyr185), P-c-Jun(Ser63) andP-IRS-1(Ser307) in hypoxia offspring (all P<0.05). Moreover, a positive interaction effectbetween prenatal hypoxia and hyperlipidemia was found (P<0.05).Conclusions：Our study results suggested that a maternal hypoxic environment could modifythe expression of adipocytokine Sfrp5and modulate the insulin sensitivity through Wnt/JNKsignaling pathway. Thus, prenatal hypoxia may provide an underlying mechanism for thedevelopment of insulin resistance, therefore serve as a novel risk factor for metabolicsyndrome. Furthermore, the effects of prenatal hypoxia were augmented by hyperlipidemiainduced by a high-fat diet. Therefore, it is necessary to pay more attention to the fetalnutrition and oxygen supply in utero, so as to prevent chronic disease during adulthood, forexample, the early onset of insulin resistance.