Origins and consequences of altered metabolic processes in obese pregnant women
Barr, Sarah Marie
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Maternal obesity is an increasing concern in the obstetric population. It confers increased morbidity and mortality to the mother and offspring during pregnancy and delivery as well as potential long-term increase in risk of ill health to the offspring. There are currently few effective interventions and no pharmacological therapies. Potential mechanisms to account for ill health in obese non-pregnant individuals include excess inflammation, both systemically and within specific tissues such as adipose, as well as alterations in metabolic regulation including hyperglycaemia, reduced sensitivity to insulin and altered adipokine expression. In healthy pregnancy, there are significant adaptations to maternal metabolism, including the development of profound systemic insulin resistance. We hypothesize that there exists an interaction between the metabolic adaptations of pregnancy and those occurring in obesity which could provide a physiologically plausible mechanism which could contribute to the pathogenesis of adverse outcomes associated with obese pregnancies. In this thesis, we sought to understand and define the metabolic adaptations to pregnancy in severely obese women. Anthropometric characteristics are described in a longitudinal case-control study of apparently healthy obese (BMI > 40kg/m2) pregnant women. Systemic adipokine and pro- inflammatory cytokine profiles were measuring using ELISA. Indices of insulin sensitivity were assessed at three time points in pregnancy. In a cohort study of healthy pregnant women in the third trimester, transcript levels of adipokines and inflammatory cytokines in paired subcutaneous and omental adipose tissue biopsies were quantified and correlated these transcript levels with booking body mass index (BMI). Obese pregnant women gained less weight in pregnancy compared to lean women, but had significantly elevated fasting third trimester glucose, as well as elevated blood pressure and fasting insulin resistance throughout pregnancy. Fasting leptin was elevated throughout pregnancy in obese compared with lean pregnancy women; however, in the third trimester there was no correlation between adipose tissue leptin mRNA levels and BMI. Transcript levels of IL-6 were positively correlated with BMI in subcutaneous but not omental adipose tissue; no other positive correlations with BMI were shown. Hyperinsulinaemic euglycaemic clamps with concomitant use of stable isotope tracers were carried out in a case-control study of healthy obese pregnant women to characterise in detail whole body insulin sensitivity, endogenous glucose production and rate of lipolysis. In contrast to the original hypothesis, by the third trimester, there were few differences between lean and obese pregnant women in whole body glucose disposal (WGD) and endogenous glucose production. Compared with non-pregnant women, lean pregnant women demonstrated approximately 60% decrement in WGD; in contrast, obese non-pregnant women were already significantly insulin resistant but did not develop further insulin resistance in response to pregnancy. 3-Tesla (3T) Magnetic Resonance Imaging (MRI) and 1H-Magnetic Resonance Spectroscopy (1H-MRS)was used to assess abdominal fat distribution, hepatic and skeletal muscle lipid content in a case-control study of healthy pregnant women in the third trimester. As expected, obese pregnant women have greater adipose accumulation in both subcutaneous and intra-abdominal adipose depots and greater lipid accumulation in skeletal muscle. However, hepatic lipid content was low in both groups and there were no significant differences between lean and obese pregnant women. This was not expected as both groups are profoundly insulin resistant at this at this gestation, and in non-pregnant individuals, insulin resistance at this level would be expected to drive hepatic lipid accumulation, and may point to a pregnancyspecific hepato-protective mechanism. In conclusion, in this thesis, it has been shown that while obese women are insulin resistant with an adverse metabolic profile, that there does not appear to be the expected worsening of this profile in response to pregnancy and that by the end of pregnancy, lean women have a similar phenotype. Instead, while lean women are exposed to this environment only towards the end of pregnancy, obese women and their offspring are exposed throughout gestation, including key periods of fetal development in early pregnancy. This prolonged exposure may account for the excess pathologies in such pregnancies, potentially by exhausting what physiological reserve such women have pre-pregnancy. Potential therapies must therefore be optimally timed to improve the metabolic profile of obese women in early pregnancy, without hindering the required adaptations of the third trimester.