Introduction: In a well-established model of murine diet-induced maternal obesity, offspring of obese dams show age-dependent and sex-specific cardiac hypertrophy and contractile dysfunction. While alterations in energy metabolism and myocardial substrate preference are associated with pathophysiological changes in cardiac function, programmed changes in offspring cardiac metabolism in response to maternal obesity remain incompletely defined. Recent studies have highlighted altered metabolic gene expression in the hearts of offspring of obese pregnancy, both in late fetal life and adulthood, however the impact on mitochondrial respiratory function in the developing and adult heart is unclear.
Objective: To evaluate myocardial mitochondrial respiratory capacity and metabolic substrate preference in young adult offspring born to obese dams in a well-established murine model of diet-induced maternal obesity.
Methods: Animal work received ethical approval from the University of Cambridge Animal Welfare and Ethical Review Board and was performed in accordance with UK Home Office guidelines under the Animals (Scientific Procedures) Act 1986. Cardiac tissue was collected from 8 week old C57BL/6J mice of both sexes born to dams fed either a control or obesogenic diet for 10 weeks prior to mating and throughout gestation and lactation, with all offspring subsequently weaned onto control diet. Mitochondrial electron transfer system (ETS) capacity was assessed using a protocol optimised for frozen samples. Respiratory complex subunit levels were measured by immunoblotting, and gene expression by RT-qPCR. Data was analysed by two-way ANOVA for sex and maternal diet, with Tukey post-hoc testing where p(Interaction) < 0.05 (n = 8).
Results: In the hearts of 8 week old offspring of obese pregnancy, myocardial mitochondrial complex I-supported respiration (relative to maximal ETS capacity) was greater than in the offspring of dams fed a control diet (control: 0.37 ±0.038 vs. obese: 0.41 ±0.065, p(Diet) = 0.041). This change in complex I-supported respiration was accompanied by an increase in NDUFA9 subunit protein levels which did not reach statistical significance (control: 0.31 ±0.002 vs. obese: 0.35 ±0.002, p(Diet) = 0.063). In the hearts of the offspring of obese dams, there was differential expression of genes encoding fatty acid oxidation associated proteins by maternal diet. Hadh expression was 1.4-fold higher in the offspring of obese pregnancy compared with controls (p(Diet) = 0.0096). Expression of Cpt1b and Ucp3 were altered by maternal diet in a sex-specific manner, being lower in the hearts of female offspring of obese pregnancy, compared with female offspring of control pregnancy. These findings suggest sex-specific alterations in myocardial fatty acid oxidation as a result of maternal diet.
Conclusions and further work: The hearts of young adult offspring of obese dams are characterised by metabolic alterations including changes in mitochondrial respiration and fatty acid oxidation (in a sex-specific manner). Further work is underway to profile mitochondrial respiration and substrate metabolism in the cardiac tissue of neonatal offspring of obesogenic diet- and control-fed dams, in order to understand the time course of metabolic alterations in relation to cardiac development.