Sex modulates the diet-induced changes to the plasma lipidome in a rat model of cardiorespiratory fitness

Individuals with higher intrinsic cardiorespiratory fitness (CRF) experience decreased rates of cardiometabolic disease and mortality, and high CRF is associated with increased utilization of fatty acids (FAs) for energy. Studies suggest a complex relationship between CRF, diet, and sex with health outcomes, but this interaction is understudied. We hypothesized that FA utilization differences by fitness and sex could be detected in the plasma metabolome when rats or humans were fed a high carbohydrate (HC) or high fat (HF) diet. Male and female rats selectively bred for low (LCR) and high (HCR) CRF were fed a chow diet or a sucrose-free HF (45 % fat) or HC (10 % fat) diet. Plasma samples were collected at days 0, 3, and 14. Human plasma data was collected from male and female participants who were randomized into a HC or HF diet for 21 days. Samples were analyzed using liquid chromatography-mass spectrometry and regression statistics were used to quantify the effect of diet, CRF, and sex on the lipidome. In rats, the baseline lipidome is more significantly influenced by sex than by CRF, especially as elevated diglycerides, triglycerides, phosphatidylcholines, and lysophosphatidylcholines in males. A dynamic response to diet was observed 3 days after diet, but after 14 days of either diet, the lipidome was modulated by sex with a larger effect size than by diet. Data from the human study also suggests a sex-dependent response to diet with opposite directionality of affect compared to rats, highlighting species-dependent responses to dietary intervention. •Biological sex modulates the plasma lipidome response to diet in rats and humans.•Male rats have higher plasma triglycerides and diglycerides than female rats.•The lipidomic response to novel diets is dynamic and adapts over time.•Dietary fat affected body weight while carbohydrate affected insulin levels.•Intrinsic aerobic fitness minimally affects the plasma lipidome in a rat model.