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

• Published in: International Journal of Obesity Vol. 44; no. 2; pp. 488 - 499
• Main Authors: Vaughan, Owen R., Rosario, Fredrick J., Powell, Theresa L., Jansson, Thomas
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.02.2020; Nature Publishing Group
• Subjects: 38/77; 59; 631/443/319/1642/393; 64/60; 692/699/2743/393; 82/80; 96/95; Actin; Adiponectin; Adiponectin - administration & dosage; Adiponectin - blood; Adiponectin - pharmacology; Age; AKT protein; Animals; Brain natriuretic peptide; Cardiomyocytes; Collagen; Echocardiography; Epidemiology; Extracellular signal-regulated kinase; Female; Females; Gene expression; Genetic crosses; Health Promotion and Disease Prevention; Heart - diagnostic imaging; Heart - physiopathology; Heart Diseases - prevention & control; Hypertrophy; Internal Medicine; Kinases; Male; Maternal Nutritional Physiological Phenomena - drug effects; Medicine; Medicine & Public Health; Metabolic Diseases; Metabolic disorders; Metabolic syndrome; Mice; Mice, Inbred C57BL; Mice, Obese; Muscle proteins; Myocardium - pathology; Natriuretic peptides; Obesity; Offspring; Placenta; Pregnancy; Pregnant women; Prenatal Exposure Delayed Effects - prevention & control; Public Health; Rapamycin; Signaling; TOR protein; Ventricle; Wall thickness
• ISSN: 0307-0565; 1476-5497
• DOI: 10.1038/s41366-019-0374-4

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.