Bioenergetic and Metabolic Signatures of Maternal Overnutrition in the Offspring Heart

The growing global incidence of obesity among women of childbearing age has concerning implications for offspring longitudinal health outcomes. In human populations, maternal obesity is associated with a heightened predisposition of offspring towards cardiometabolic disease, whilst hearts of mice born to obese dams exhibit hypertrophic remodelling and contractile dysfunction. Programmed alterations in mitochondrial respiratory function, substrate metabolism and oxidative stress have been implicated in offspring cardiac alterations, however these bioenergetic and metabolic phenotypes remain poorly defined. This thesis aimed to investigate cardiac mitochondrial bioenergetics and metabolism in the offspring of overnourished mothers using mouse and sheep models, alongside other tissues relevant to whole- body metabolic status. In the hearts of 8-week-old offspring from a murine model of diet-induced maternal obesity, relative activity and expression of electron transfer system (ETS) complex I was enhanced. This was accompanied by increased glycolytic gene expression. Neither cardiac mitochondrial substrate preference nor total respiratory capacity was altered in pups of overnourished dams at postnatal day 3 (PND3), however mitochondrial ADP sensitivity was heightened in these pups. To contextualise the cardiac phenotype against broader metabolic dyshomeostasis, the impact of maternal overnutrition on hepatic mitochondrial respiratory function and metabolism was also assessed. Maternal obesity exposure lowered mitochondrial ETS capacity in young adult offspring. Whilst hepatic triglyceride content was unchanged by maternal diet, lipid metabolic gene expression was remodelled in obese-exposed vs. control females, which may confer sex- specific, longitudinal protection against steatosis. No differences in respiratory capacity were observed in the livers of PND3 pups, implicating contributions of ageing and lactational environment to the adult phenotype. Mitochondrial respiratory function was further assessed in heart, placenta, perirenal adipose, and liver of late-gestational sheep fetuses from a novel ovine maternal obesity model. Maternal obesity suppressed respiratory capacity in male fetal hearts, and lowered succinate-supported respiration in obese-exposed females. Cardiac ADP sensitivity was blunted by maternal obesity, but rescued in the presence of creatine, suggesting premature compartmentation of ADP channelling. Maternal obesity was also associated with male-specific suppression of complex I- linked respiration in the placenta, suggesting a shared aetiology of male-biased mitochondrial effects in fetal heart and placenta. Perirenal adipose tissue displayed lowered UCP1 activity, indicative of brown adipose whitening. The mitochondrial effects of the microRNA miR-15b-5p, a prospective molecular mediator of metabolic reprogramming in hearts of obese-exposed adult male mice were assessed in vitro. miR-15b-5p-transfection of H9c2 cardiac myoblasts resulted in lower cellular viability and heightened sensitivity to OMM permeabilisation, suggestive of apoptotic sensitisation. Together, this work demonstrates sensitivity of offspring cardiac ETS organisation, substrate metabolism, and adenine nucleotide homeostasis to maternal overnutrition. These changes are not necessarily consistent between early life and adulthood and vary between precocial and altricial model species, challenging the notion of a consistently programmed cardiac mitochondrial phenotype.

Name dc:type.qualificationname

Doctor of Philosophy (PhD)

Level dc:type.qualificationlevel

Doctoral

Grantor dc:publisher.institution

University of Cambridge

Year dc:date.issued

2025

Author dc:creator

• Thackray, Benjamin

Advisors dc:contributor.advisor

• Murray, Andrew
• Ozanne, Susan

• Metabolism
• Developmental programming
• Maternal obesity
• Cardiac metabolism
• Mitochondrial function

Licence

• https://www.repository.cam.ac.uk/bitstreams/fb831127-fab1-4ef4-bfd8-8ff59787a1f2/download
• http://purl.org/NET/rdflicense/allrightsreserved

Language dc:language

eng

DOI dc:identifier.doi

https://doi.org/10.17863/CAM.126608

OAI identifier oai:identifier

oai:www.repository.cam.ac.uk:1810/397478