Sex differences in cardiac hypertrophy are linked to adipose tissue lipolysis

Adipose tissue (AT) undergoes profound molecular changes during exercise. Women exhibit enhanced exercise-mediated AT-lipolysis when compared to men. Exercise-induced cardiac hypertrophy has been recently identified to be regulated in a sex-specific manner. The aim of the project was to investigate the influence of sex-specific differences in AT-lipolytic activity on exercise-induced cardiac hypertrophy.

Female and male C57BL/6J mice were challenged with active treadmill running for 1.5h/day (0.25m/s) over 4 weeks. Mice underwent cardiac and metabolic phenotyping including echocardiography, small-animal PET, and peri-exercise indirect calorimetry. Female mice exhibited increased cardiac hypertrophic responses to exercise when compared to male mice, measured by echocardiography (percent increase in left ventricular mass (LVM): female: 22.2±0.8%, male: 9.0±0.2%; p<0.05). This was associated with increased plasma FFA levels in female mice after training, whereas FFA levels from male mice decreased. Also the respiratory quotient during exercise was significantly lower in female mice indicative for preferential utilization of fatty acids. This was associated with elevated ATGL expression level in female AT. As a result of sex-mediated differences in substrate availability and utilization, myocardial glucose uptake was reduced in female mice after exercise, analyzed by PET (injection dose (ID)/LVM [%ID/g]: 36.8±3.5 (female sedentary vs. 28.3±4.3 female training, p<0.05), whereas cardiac glucose uptake was unaltered after exercise in male counterparts

Collectively, our data demonstrate that sex-specific modulation of fatty-acid metabolism during exercise is associated with sexual dimorphic changes in cardiac substrate utilization and exercise-induced cardiac hypertrophy.