The effects of maternal hypoxia on pregnancy outcome, lipid and glucose metabolism and gestational diabetes

Abstract At high altitudes, chronic hypoxia challenges fetal growth leading to decreased birth weight which increases the perinatal mortality and morbidity and predisposes to cardiovascular and metabolic diseases later in life. On the other hand, also fetal macrosomia increases the risk for metabolic dysfunctions. Major causes of fetal macrosomia are gestational diabetes mellitus (GDM) and maternal overweight. GDM is a global problem affecting up to 30% of pregnancies and increasing morbidity of mothers and offspring. In cellular level, hypoxia response is mediated by hypoxia-inducible factor (HIF), a heterodimeric transcription factor regulating the transcription of over 300 genes targeting e.g., energy metabolism and erythropoiesis. In an oxygenated environment, HIF prolyl 4-hydroxylases (HIF-P4Hs) target the HIFα subunit to proteasomal degradation. HIF-P4H inhibitors, recently approved for treatment of renal anemia, activate the HIF response. Anemic patients treated with HIF-P4H inhibitors exhibit improved cardiometabolic health. Furthermore, preclinical mouse models show improved glucose tolerance, reduced insulin resistance (IR) and protection against metabolic syndrome with HIF-P4H inhibition. Hemoglobin (Hb) is the most important transporter of oxygen in the body. Low-end normal Hb levels have been shown to act as a surrogate marker for activation of HIF response and to associate with better metabolic health. Here we unraveled the effects of environmental hypoxia (15% O2) on pregnant dams’ glucose and lipid metabolism in mice and found that improved glucose tolerance, decreased IR and a lower amount of white adipose tissue led to decreased embryo weight. Next, we examined whether 15% O2 could protect obese mice from the development of GDM. We discovered clear improvement of maternal metabolism by hypoxia but detrimental effects on the feto-placental unit. When assessing the association of the 1st trimester Hb levels with GDM risk in a Finnish multicenter case-control study for GDM (FinnGeDi), we found that the low-end normal Hb levels decreased the risk for GDM without an adverse effect on fetal outcome. The results of this thesis shed light on maternal gestational metabolism in a hypoxic environment, identify risk factors for GDM in the Finnish population and provide information for the development of novel treatment options for GDM.Tiivistelmä Kudosten hapenpuute eli hypoksia vaikeuttaa sikiönkehitystä erityisesti vuoristoalueilla, joissa hapen määrä on alentunut, johtaen alentuneeseen syntymäpainoon. Tämä lisää akuutisti kuolleisuutta ja sairastavuutta sekä altistaa metabolisille ongelmille ja sydän- ja verisuonisairauksille. Toisaalta myös sikiön liikakasvu lisää aineenvaihdunnan ongelmien riskiä. Merkittäviä syitä sikiön liikakasvun taustalla ovat raskausdiabetes (GDM) sekä äidin ylipaino. GDM on globaali ongelma, vaikuttaen jopa 30 %:in raskauksista lisäten äitien ja lasten sairastuvuutta. Hapenpuute johtaa hypoksiavasteen aktivaatioon. Tätä välittää hypoksiassa indusoituva tekijä (HIF), joka säätelee esimerkiksi energia-aineenvaihduntaa ja punasolujen kypsymistä yli 300 geenin välityksellä. HIF on transkriptiotekijä, joka koostuu kahdesta alayksiköstä: HIFβ:sta sekä happipitoisessa ympäristössä HIF prolyyli-4-hydroksylaasien (HIF-P4H) avulla hajotukseen ohjattavasta HIFα:sta. HIF-P4H estäjät aktivoivat HIF-vasteen ja niitä käytetään munuaisperäisen anemian hoitoon. HIF-P4H estäjillä hoidetuilla anemiapotilailla on havaittu parantunut kardiometabolinen terveys ja hiirikokeissa vastaavasti parantunut sokerinsieto, vähentynyt insuliiniresistenssi (IR) sekä suoja metaboliselta oireyhtymältä. Elimistön tärkein hapenkuljettaja on hemoglobiini (Hb). Väestön normaalivaihtelun sisällä matalan Hb:n on osoitettu välittävän matala-asteista HIF-vastetta ja liittyvän parantuneeseen metaboliseen terveyteen. Ensimmäisessä osatyössä selvitettiin ympäristön hypoksian vaikutusta raskaana olevan emon energia-aineenvaihduntaan hiirillä, ja havaittiin parantuneen sokerinsiedon, vähentyneen IR:n sekä pienentyneen rasvakudoksen määrän johtavan alentuneeseen syntymäpainoon. Toisessa osatyössä selvitettiin, voisiko ympäristön hypoksia suojata ylipainoisia hiiriä GDM:lta. Siinä havaittiin emon sokeriaineenvaihdunnan selkeä paraneminen, mutta poikasten kasvu häiriintyi. Toisaalta kolmannessa osatyössä äidin alkuraskauden matalampien Hb-tasojen havaittiin pienentävän GDM:n riskiä vaikuttamatta sikiön kasvuun suomalaisessa raskausdiabeteksen tapaus-verrokkitutkimuksessa. Tämän työn tulokset valottavat raskaudenaikaista aineenvaihduntaa hypoksisissa olosuhteissa sekä tarjoavat uutta tietoa GDM:lle altistavista tekijöistä suomalaisessa väestössä ja mahdollisista uusista hoitomenetelmistä

Hypoxia causes reductions in birth weight by altering maternal glucose and lipid metabolism

Abstract Hypoxia of residence at high altitude (>2500 m) decreases birth weight. Lower birth weight associates with infant mortality and morbidity and increased susceptibility to later-in-life cardiovascular and metabolic diseases. We sought to determine the effects of hypoxia on maternal glucose and lipid metabolism and their contributions to fetal weight. C57BL6/NCrl mice, housed throughout gestation in normobaric hypoxia (15% oxygen) or normoxia, were studied at mid (E9.5) or late gestation (E17.5). Fetal weight at E17.5 was 7% lower under hypoxia than normoxia. The hypoxic compared with normoxic dams had ~20% less gonadal white adipose tissue at mid and late gestation. The hypoxic dams had better glucose tolerance and insulin sensitivity compared with normoxic dams and failed to develop insulin resistance in late gestation. They also had increased glucagon levels. Glucose uptake to most maternal tissues was ~2-fold greater in the hypoxic than normoxic dams. The alterations in maternal metabolism in hypoxia were associated with upregulation of hypoxia-inducible factor (HIF) target genes that serve, in turn, to increase glycolytic metabolism. We conclude that environmental hypoxia alters maternal metabolism by upregulating the HIF-pathway, and suggest that interventions that antagonize such changes in metabolism in high-altitude pregnancy may be helpful for preserving fetal growth

Hypoxia ameliorates maternal diet-induced insulin resistance during pregnancy while having a detrimental effect on the placenta

Abstract Maternal overweight/obesity contributes significantly to the development of gestational diabetes, which causes risks to both mother and fetus and is increasing sharply in prevalence worldwide. Since hypoxia reprograms energy metabolism and can alleviate weight gain, adiposity, insulin resistance (IR), and dyslipidemia, we set out to study the potential of sustained reduced ambient oxygen tension (15% O2) during pregnancy for alleviating the detrimental effects of diet-induced IR in C57Bl/6N mice, taking normal chow-fed and normoxia (21% O2) groups as controls. Our data show that hypoxic intervention reduced maternal weight gain, adiposity, and adipose tissue inflammation, and ameliorated maternal glucose metabolism and IR during gestation in diet-induced IR relative to normoxia. Where diet-induced IR reduced maternal hemoglobin and increased serum erythropoietin levels, hypoxic intervention compensated for these changes. Diet-induced IR reduced fetal growth in normoxia, and even more in hypoxia. Hypoxic intervention reduced liver weight gain during pregnancy in the dams with diet-induced IR, maternal liver weight being positively associated with embryo number. In case of diet-induced IR, the hypoxic intervention compromised placental energy metabolism and vascularization and increased end-pregnancy placental necrosis. Altogether, these data show that although hypoxic intervention mediates several beneficial effects on maternal metabolism, the combination of it with diet-induced IR is even more detrimental to the placental and fetal outcome than diet-induced IR alone