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. 2020 Feb;44(2):488-499.
doi: 10.1038/s41366-019-0374-4. Epub 2019 May 10.

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

Owen R Vaughan  1 , Fredrick J Rosario  2 , Theresa L Powell  2   3 , Thomas Jansson  2
Affiliations

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

Owen R Vaughan et al. Int J Obes (Lond). 2020 Feb.

Abstract

Background/objectives: Adiponectin 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/methods: Pregnant 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.

Results: Maternal 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.

Conclusions: Low 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.

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Conflict of interest statement

The authors declare that they have no conflict of interest.

Figures

Fig. 1
Fig. 1
Cardiac diastolic function in 3- and 6-month-old offspring. Mean ± SEM echocardiographic indices of diastolic function in 3- and 6-month-old male (n = 7–9, a–c) and female (n = 6–10, d–f) offspring of control, phosphate-buffered saline (PBS)-infused pregnant mice (C/PBS) and obese pregnant mice infused either with PBS (Ob/PBS) or adiponectin (Ob/AND) from E14.5 to 18.5. y Axes represent dimensionless ratios of velocities (mm s−1) of early-diastolic mitral inflow and ventricular wall displacement (E/E’), early- and late-diastolic ventricular wall displacement (E’/A’) and early- and late-diastolic mitral inflow (E/A). Overall effect of maternal treatment group, determined by one-way analysis of variance at each offspring age, given in figure. Values with different superscripts, a or b, are significantly different from one another by pairwise post hoc comparison (P < 0.05, Holm–Sidak test)
Fig. 2
Fig. 2
Cardiomyocyte cross-sectional area in 3-month-old offspring. Representative images of wheat-germ agglutinin-stained transverse cardiac sections (a, c) and mean ± SEM cardiomyocyte cross-sectional area in 3-month old male (n = 7–10, b) and female (n = 5–10, d) offspring of control, phosphate-buffered saline (PBS)-infused pregnant mice (C/PBS) and obese pregnant mice infused either with PBS (Ob/PBS) or adiponectin (Ob/AND) from E14.5 to 18.5. Image scale bars represent 50 μM. Overall effect of maternal treatment group by one-way analysis of variance given in figure. Values with different superscripts, a or b, are significantly different from one another by pairwise post hoc comparison (P < 0.05, Holm–Sidak test)
Fig. 3
Fig. 3
Cardiac foetal gene programme expression in 3-month-old offspring. Mean ± SEM relative expression of cardiac foetal genes indicative of pathological hypertrophy in the hearts of 3-month-old male (a–d, n = 12–15) and female (e–h, n = 8–11) offspring of control, phosphate-buffered saline (PBS)-infused pregnant mice (C/PBS) and obese pregnant mice infused either with PBS (Ob/PBS) or adiponectin (Ob/AND) from E14.5 to 18.5. Overall effect of maternal treatment group by one-way analysis of variance (ANOVA) given in figure. Values with different superscripts, a or b, are significantly different from one another by pairwise post hoc comparison (P < 0.05, Holm–Sidak test). Relative expression values of omitted outliers (Grubbs’ test): a C/PBS 3.65, Ob/PBS 10.96; b C/PBS 4.53, Ob/PBS 0.45; c C/PBS 3.62, Ob/PBS 21.34; d Ob/PBS 38.22; e C/PBS 3.13, Ob/ADN 12.38; f Ob/ADN 28.43; h Ob/ADN 120.77. Hash (#) indicates ANOVA performed on log-transformed data
Fig. 4
Fig. 4
Cardiac Akt, mammalian target of rapamycin, p38 mitogen-activated protein kinase (MAPK) and extracellular signal-regulated kinase 1/2 (ERK1/2) signalling in 3-month-old offspring. a Representative bands from one western blot for each protein analysed. b, c Mean ± SEM relative abundance of total and phosphorylated forms of Akt, S6 ribosomal protein, 4EBP1, p38 MAPK and ERK1/2 proteins in the heart of 3-month-old male (n = 10–11, b) and female (n = 7–8, c) offspring of control, phosphate-buffered saline (PBS)-infused pregnant mice (C/PBS) and obese pregnant mice infused either with PBS (Ob/PBS) or adiponectin (Ob/AND) from E14.5 to 18.5. Values in bold indicate significant overall effect of maternal treatment group by one-way analysis of variance. Values with different superscripts, a or b, are significantly different from one another by pairwise post hoc comparison (P < 0.05, Holm–Sidak test)
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