Normalisation of circulating adiponectin levels in obese pregnant mice prevents cardiac dysfunction in adult offspring

Owen R Vaughan,Thomas Jansson,Fredrick J Rosario,Theresa L Powell

doi:10.1038/s41366-019-0374-4

Owen R Vaughan, Thomas Jansson + Show 2 more

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https://doi.org/10.1038/s41366-019-0374-4

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Abstract

Background/objectivesAdiponectin concentrations are low in obese pregnant women. Restoring normal adiponectin concentrations by infusion in obese pregnant mice prevents placental dysfunction, foetal overgrowth and metabolic syndrome in the offspring. We hypothesised that normalising maternal adiponectin in obese late pregnant dams prevents cardiac dysfunction in the adult offspring.Subjects/methodsPregnant female mice with diet-induced obesity were infused with adiponectin (0.62 μg g−1 day−1, n = 24) or saline (n = 22) over days 14.5–18.5 of pregnancy (term = day 19.5). Control dams ate standard chow and received saline (n = 22). Offspring were studied at 3 and 6 months of age.ResultsMaternal obesity impaired ventricular diastolic function, increased cardiomyocyte cross-sectional area and upregulated cardiac brain natriuretic peptide (Nppb) and α-skeletal actin (Acta1) gene expression in adult male offspring, compared to control offspring. In adult female offspring, maternal obesity increased Nppb expression, decreased end-diastolic volume and caused age-dependent diastolic dysfunction but not cardiomyocyte hypertrophy. Maternal obesity also activated cardiac Akt and mechanistic target of rapamycin (mTOR) signalling in male, but not in female, offspring and inhibited cardiac extracellular signal-regulated kinase 1/2 (ERK1/2) in both sexes. Normalising maternal circulating adiponectin concentrations by infusing obese dams with adiponectin prevented offspring diastolic dysfunction and ventricular dilation and normalised cardiac Akt-mTOR signalling irrespective of sex. Maternal adiponectin infusion also reduced cardiac Nppb expression and increased ERK1/2 signalling in offspring of obese dams. Adiponectin infusion did not prevent cardiomyocyte hypertrophy but reduced ventricular wall thickness in male offspring and increased collagen content in female offspring of obese dams, compared to controls.ConclusionsLow maternal adiponectin levels in obese mice in late pregnancy are mechanistically linked to in utero programming of cardiac dysfunction in their offspring. Interventions enhancing endogenous adiponectin secretion or signalling in obese pregnant women could prevent the development of cardiac dysfunction in their children.

Highlights

Supplementary information The online version of this article contains supplementary material, which is available to authorized users.Over half of women enter pregnancy overweight or obese [1, 2]
Cardiac protein kinase B (Akt), mechanistic target of rapamycin, extracellular signalregulated kinase 1/2 (ERK1/2) and mitogen-activated protein kinase (MAPK) signalling pathways are activated in offspring of obese dams [11, 13, 14]. These findings suggest that cardiomyocyte hypertrophy occurs in foetuses of obese mothers and is linked to the over-abundant supply of nutrients and elevated concentrations of insulin and other growth-promoting hormones in utero [11, 13, 14]
There was no effect of maternal obesity or adiponectin infusion on left ventricular early and late diastolic inflow velocity (E/A) ratio, wall thickness or end-systolic volume in the 3-month-old offspring of C/phosphate-buffered saline (PBS), Ob/PBS and Ob/ADN dams (Fig. 1 and Table 1)

Summary

Introduction

Over half of women enter pregnancy overweight or obese [1, 2]. High maternal pre-pregnancy body mass index is associated with impaired ventricular function and septal thickening in the first trimester foetus [6] and reduced diastolic function near term [7]. The risk for eccentric left ventricular hypertrophy at 6 years of age is greater in the children of obese women [8, 9]. Dietinduced obesity in pregnant experimental animals induces offspring cardiac hypertrophy and impaired cardiac function both before and after birth [10,11,12,13,14]. Maternal obesity increases cardiac weight, wall thickness, Normalisation of circulating adiponectin levels in obese pregnant mice prevents cardiac dysfunction in

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