Abstract
Maternal obesity is linked with increased adverse pregnancy outcomes for both mother and child. The metabolic impact of excessive fat within the context of pregnancy is not fully understood. We used a mouse model of high fat (HF) feeding to induce maternal obesity to identify adipose tissue-mediated mechanisms driving metabolic dysfunction in pregnant and non-pregnant obese mice. As expected, chronic HF-feeding for 12 weeks preceding pregnancy increased peripheral (subcutaneous) and visceral (mesenteric) fat mass. However, unexpectedly at late gestation (E18.5) HF-fed mice exhibited a remarkable normalization of visceral but not peripheral adiposity, with a 53% reduction in non-pregnant visceral fat mass expressed as a proportion of body weight (P<0.001). In contrast, in control animals, pregnancy had no effect on visceral fat mass proportion. Obesity exaggerated glucose intolerance at mid-pregnancy (E14.5). However by E18.5, there were no differences, in glucose tolerance between obese and control mice. Transcriptomic analysis of visceral fat from HF-fed dams at E18.5 revealed reduced expression of genes involved in de novo lipogenesis (diacylglycerol O-acyltransferase 2 - Dgat2) and inflammation (chemokine C-C motif ligand 2 - Ccl2) and upregulation of estrogen receptor α (ERα) compared to HF non pregnant. Attenuation of adipose inflammation was functionally confirmed by a 45% reduction of CD11b+CD11c+ adipose tissue macrophages (expressed as a proportion of all stromal vascular fraction cells) in HF pregnant compared to HF non pregnant animals (P<0.001). An ERα selective agonist suppressed both de novo lipogenesis and expression of lipogenic genes in adipocytes in vitro. These data show that, in a HF model of maternal obesity, late gestation is associated with amelioration of visceral fat hypertrophy, inflammation and glucose intolerance, and suggest that these effects are mediated in part by elevated visceral adipocyte ERα signaling.
Highlights
Obesity is an important risk factor for adverse pregnancy outcomes for the mother, and the baby [1]
High fat (HF) feeding for 12 weeks resulted in a 30% increase in body weight in female mice (Figure 1A) which was in agreement with previous studies from our laboratory using this model [17]
Our key and unexpected observation is the inhibition of the progressive worsening of visceral adiposity, inflammation and metabolic dysfunction observed during normal pregnancy when mice are fed a high fat (HF) diet prior to and throughout gestation
Summary
Obesity is an important risk factor for adverse pregnancy outcomes for the mother, (eg preeclampsia, gestational diabetes, caesarean section) and the baby (eg miscarriage, stillbirth and macrosomia) [1]. Many effect of pregnancy on maternal metabolism have been defined, the interactions between obesity and pregnancy on adipose tissue function, which plays an essential role on metabolism, are incompletely understood. Improvements in understanding the impact of pregnancy on adipose tissue metabolism in obese pregnant women could aid the development of therapies to reduce the risk of adverse pregnancy outcome in obesity. In order to address this issue, we performed a detailed phenotyping study using a high fat (HF) fed murine model of obesity, together with a transcriptomic and an in vitro functional analysis of visceral fat to identify adipose tissue-mediated mechanisms driving metabolic dysfunction in obese and lean pregnancy
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