Previous studies suggest that sex differences in lipid metabolism exist with females demonstrating a higher utilization of lipids during exercise, which is mediated partly by increased utilization of muscle triglycerides. However, whether these changes in lipid metabolism contribute directly to endurance exercise performance is unclear. Therefore, the objective of this study was to investigate the contribution of exercise substrate metabolism to sex differences in endurance exercise capacity (EEC) in mice. Male and female C57BL/6‐NCrl mice were subjected to an EEC test until exhaustion on a motorized treadmill. The treadmill was set at a 10% incline, and the speed gradually increased from 10.2 m/min to 22.2 m/min at fixed intervals for up to 2.5 h. Tissues and blood were harvested in mice immediately following the EEC. A cohort of sedentary, non‐exercised male and female mice were used as controls. Females outperformed males by ~25% on the EEC. Serum levels of both fatty acids and ketone bodies were ~50% higher in females at the end of the EEC. In sedentary female mice, skeletal muscle triglyceride content was significantly greater compared to sedentary males. Gene expression analysis demonstrated that genes involved in skeletal muscle fatty acid oxidation were significantly higher in females with no changes in genes associated with glucose uptake or ketone body oxidation. The findings suggest that female mice have a higher endurance exercise capacity and a greater ability to mobilize and utilize fatty acids for energy.

The promotion of ketone body (KB) metabolism via ketosis has been suggested as a strategy to increase exercise performance. However, studies in humans and animals have yielded inconsistent results. The purpose of the current study was to examine the effects of ketosis, achieved via fasting or a short-term ketogenic diet (KD), on endurance exercise performance in female mice. After 8 h of fasting, serum KB significantly increased and serum glucose significantly decreased in fasted compared to fed mice. When subjected to an endurance exercise capacity (EEC) test on a motorized treadmill, both fed and fasted mice showed similar EEC performance. A 5-week KD (90% calories from fat) significantly increased serum KB but did not increase EEC times compared to chow-fed mice. KD mice gained significantly more weight than chow-fed mice and had greater adipose tissue mass. Biochemical tissue analysis showed that KD led to significant increases in triglyceride content in the heart and liver and significant decreases in glycogen content in the muscle and liver. Furthermore, KD downregulated genes involved in glucose and KB oxidation and upregulated genes involved in lipid metabolism in the heart. These findings suggest that a short-term KD is not an effective strategy to enhance exercise performance and may lead to increased adiposity, abnormal endogenous tissue storage, and cardiometabolic remodeling.

The investigation of sex‐specific differences in physiological and pathophysiological processes is of increased importance in scientific research. Previous studies, in both rodents and humans, observed that females generally have a higher endurance exercise capacity (EEC) than males. Additional research suggests that the increased EEC in females is mediated, in part, by differences in substrate metabolism during exercise. The objective of this study was to determine whether changes in exercise substrate metabolism contributed to sex‐specific differences in EEC in mice. To evaluate EEC, male and female, C57BL/6‐NCrl mice (n=9 each group) were subjected to a graded exercise test on a motorized treadmill. The treadmill was set at a 10% incline and the speed gradually increased from 10.2 m/min to 22.2 m/min at fixed intervals for up to 2.5 hrs. At exhaustion, blood glucose (BG) was measured from a tail clip using a hand‐held glucometer. Blood and tissues (heart, liver, skeletal muscle, and adipose) were harvested from all mice. Serum levels of non‐esterified fatty acids (NEFA), triglycerides (TG), cholesterol (CHOL), lactate (LAC), and ketone bodies (KET) were measured using commercially available kits. Endurance exercise times were ~25% higher in females compared to males (121.2 ± 4.0 min vs. 97.3 ± 4.3 min, P<0.05). At exhaustion, BG was significantly lower in females (66.7 ± 3.0 mg/dl) vs. males (75.8 ± 2.4 mg/dl); however, there was no significant difference in LAC. Although post‐exercise serum TG levels were similar, CHOL was significantly lower in females (40.3 ± 2.5 mg/dl vs. 50.6 ± 3.0 mg/dl). Interestingly, serum levels of both NEFA and KET were ~50% higher in females at exhaustion. Although body weight was significantly greater in males (25.6 ± 0.8g vs. 20.1 ± 0.6g), the quadriceps to body weight ratio was similar, suggesting that body or muscle mass was not a factor in the differences. In conclusion, female mice have higher EEC than male mice, which may be due to the supply of exogenous substrates. In particular, female mice have elevated serum levels of fatty acids and ketone bodies at exhaustion, which may reflect an increased ability to mobilize these substrates to prolong endurance exercise. Additional studies will investigate whether endogenous cellular metabolism, especially glycogen and triglycerides in skeletal muscle, contribute to the enhanced endurance capacity phenotype.Support or Funding InformationThis work was supported by funding from the American Heart Association and Ursinus College.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Excessive consumption of unsaturated or saturated fatty acids have adverse effects on certain health parameters, namely increased risk of obesity, diabetes, and cardiovascular disease. Specifically, saturated fats are linked to increased cardiovascular risk while unsaturated fats are suggested to protect against cardiovascular disease. Our previous work suggested that various high fat diets have differential effects on cardiac hypertrophy and function. However, it was not clear whether a high saturated fat diet (HSFD) or high unsaturated fat diet (HUFD) could elicit different disease phenotypes. Therefore, the purpose of this study was to evaluate the effects of HSFD or HUFD on the development of obesity, diabetes, and cardiac lipotoxicity in mice. Male, C57BL/6J mice received normal chow (CON, n=12), HSFD (n=15) or HUFD (n=15) for 12 weeks. Body weight and food intake were measured weekly. After 12 weeks, the adipose tissue and heart were removed and weighed. Glucose, fatty acids, and cholesterol were analyzed in serum using biochemical assays. Cardiac triglycerides (TG) were measured in heart tissue extracts. Both HSFD and HUFD significantly increased body weight above CON. Interestingly, body weight increased by ~63% in the HUFD while the HSFD increased ~41% (P<0.05). Adipose tissue mass was increased 5‐fold in both HFD groups and was ~10% greater in the HUFD. Surprisingly, caloric intake was higher in the HSFD (15.3±0.8) compared to HUFD (12.8±0.1) and CON (11.9±0.7). Serum cholesterol levels were elevated in both HSFD and HUFD. Blood glucose was significantly increased only in the HUFD while serum fatty acids were increased only in the HSFD. Cardiac hypertrophy, assessed by the heart weight to tibia length ratio, was increased in the HSFD but not HUFD group. Cardiac TGs were ~25% higher in HSFD but <10% in HUFD compared to CON. These data show that excess consumption of saturated or unsaturated fats increased body weight and adiposity in mice. However, high consumption of unsaturated fatty acids resulted in a pronounced increase in body weight, body fat, and hyperglycemia, consistent with an obese and diabetic phenotype. Conversely, high consumption of saturated fatty acids caused elevated serum lipids, cardiac hypertrophy, and cardiac lipid accumulation, consistent with cardiac lipotoxicity. In conclusion, the fatty acid composition of diets may be critical in the development of disease phenotypes resulting from high fat feeding in mice.Support or Funding InformationThis work was supported by funding from the American Heart Association and Ursinus College.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.