Although exercise training is an important recommendation for the management of type 1 diabetes (T1D), most of the available research studies predominantly focus on male subjects. Given the importance of sex as a biological variable, additional studies are required to improve the knowledge gap regarding sex differences in T1D research. Therefore, the purpose of this study was to examine the role of exercise training in mediating changes in glucose homeostasis and skeletal muscle metabolism in T1D female mice. Female mice were injected with streptozotocin (STZ) to induce T1D. Two weeks after STZ injection, control (CON) and STZ mice were exercise trained on a treadmill for 4 weeks. Aerobic exercise training failed to improve glucose tolerance, prevent the decrease in body weight and adipose tissue mass, or attenuate muscle atrophy in T1D female mice. However, insulin sensitivity was improved in T1D female mice after exercise training. Aerobic exercise training maintained skeletal muscle triglyceride content but did not prevent depletion of skeletal muscle or liver glycogen in T1D mice. Gene expression analysis suggested that T1D resulted in decreased glucose transport, decreased ketone body oxidation, and increased fatty acid metabolism in the skeletal muscle, which was not altered by exercise training. These data demonstrate that 4 weeks of aerobic exercise training of a moderate intensity is insufficient to counteract the negative effects of T1D in female mice, but does lead to an improvement in insulin sensitivity.

The ketogenic diet (KD) is a high‐fat, low‐carbohydrate diet that results in the elevation of ketone bodies in the blood, known as ketosis. This metabolic consequence has been suggested as a method for treating neurological conditions, improving exercise performance, and facilitating weight loss. Since most research studies primarily use male populations, less information is available regarding potential sex differences in response to various interventions. Therefore, the purpose of this study was to explore the sex differences in physical, metabolic, and motor performance in mice fed the KD. Male (n=29) and female (n=26) C57BL/6 were randomly assigned to KD (90% fat, 1% carbohydrate) or chow (13% fat, 60% carbohydrate) group for 6 weeks. Body weight and food intake were tracked weekly. At baseline and every 2 weeks, the Rotarod performance test assessed motor coordination and activity levels in all mice. After 6 weeks, adipose tissue, quadriceps, and heart were weighed to observe changes in organ mass. Triglyceride (TG) was measured in the heart, liver, and quadriceps. Blood was drawn to measure changes in serum metabolite levels. Final body weights in Male‐KD were similar to Male‐chow; however, Female‐KD mice were significantly higher relative to Female‐chow. Although adipose tissue mass increased significantly in both KD groups, the increase was ~40% higher in Female‐KD. Quadriceps mass was lower in Male‐KD compared to Male‐chow (188±6 vs.169±5 mg, P<0.05) while not statistically different in Female‐KD relative to Female‐chow. In contrast, heart weight to tibia length ratios (HW:TL) were increased in Female‐KD compared to Female‐chow (5.08±0.06 vs.5.58±0.12, P<0.05) with no significant change in Male‐KD. The KD resulted in similar measures of ketosis, glucose intolerance, and hyperlipidemia in Male‐KD and Female‐KD. While cardiac TG content tended to increase in Male‐KD and Female‐KD to a similar extent (P<0.10), the increase in hepatic TG content was ~30% lower in Female‐KD (P<0.05 vs. Male‐KD). Although Rotarod performance was higher in Female‐KD compared to Male‐KD at week 2 (28.6±3.1 vs.15.2±1.6 sec, P<0.05), performance decreased in Female‐KD and increased in Male‐KD over the remaining weeks and was similar at week 6 (25.7±2.0 vs.20.7±2.0 sec). In summary, these data show sex specific differences in weight gain, adiposity, and muscle (i.e., cardiac and skeletal) mass changes in response to a short‐term KD. Moreover, the data suggest that male and female mice on the KD differ in time sensitive adaptation to ketosis and motor activity. Since both males and females increase adiposity, develop glucose intolerance, and hyperlipidemia, this study questions the viability of the KD as a potential tool for weight loss, and importantly, highlights sex differences in the adaptation to the KD.

Mouse models of diet‐induced obesity are commonly used for studies of metabolic disease. Since sex and strain differences are suggested to influence the results, studies have been generally limited to males of one mouse strain. This limited study population may impact the understanding of the effect of sex and genetic background on metabolic parameters. Therefore, the purpose of this study was to examine potential differences in short‐term feeding of a high fat diet in two popular strains of female mice. Ten‐week‐old, female FVB/N (FVB, n=20) and C57BL/6‐Ncrl (C57, n=20) mice were fed a Western Diet (WD; 40% calories from fat) or standard chow diet (13% calories from fat) for 6 weeks. Body weight was measured at weekly intervals and the Open Field Test (OFT) was administered to assess changes in activity and behavior at baseline and 6 weeks. The OFT consists of a circular arena, where mice were observed for 10 minutes using a video tracking software system to determine distance, speed, and motion. Tissues and blood were harvested after the 6‐week feeding period. Body weights and organ masses (i.e., heart, liver, adipose, and spleen) were significantly greater in FVB‐chow compared to C57‐chow mice. After 6‐weeks of feeding, body weights, adipose mass, and liver mass were significantly higher in FVB‐WD but not in C57‐WD compared to respective chow groups. FVB‐WD had reduced heart weight to tibial length ratios (FVB‐WD: 6.05±0.14 vs. FVB‐chow: 5.41±0.14, P<0.05) and higher serum ketone body levels compared to FVB‐chow (FVB‐WD: 0.42±0.03 vs. FVB‐chow: 0.76±0.15 mM, P<0.05), changes that were not observed in C57‐WD. OFT results revealed significant effects of diet and mouse strain. At baseline, FVB mice spent greater time moving (422± vs. 379±11 sec, P<0.05) and greater time in the border zone (515±9 vs. 452±11 sec, P<0.05) compared to C57 mice. After 6 weeks, time spent moving tended to decrease in C57‐WD compared to C57‐Chow (42% vs. 30%, P<0.10) while FVB‐WD and FVB‐chow had similar decreases (15% vs. 13% in FVB‐chow). Time in the border zone significantly increased by 8% in C57‐WD compared to a 20% decrease in C57‐chow. In contrast, border zone time decreased by 9% and 10% in FVB‐chow and FVB‐WD, respectively. In summary, in response to 6 weeks of WD, female FVB mice exhibit a more pronounced physical phenotype whereas female C57 mice are more prone to changes in activity and behavior. Overall, these results highlight important strain differences in response to a short‐term high fat diet in female mice

Ketone bodies have been identified as an important fuel source during physiological and pathological stress. During exercise, augmenting ketone body metabolism in the skeletal muscle may enhance exercise performance while targeting ketone body metabolism in cardiac disease may improve cardiac function. These provocative, yet still debated, findings may promote the consumption of the ketogenic diet (KD) as a method to increase ketone body availability. Since the KD is a high‐fat, low carbohydrate diet, this dietary strategy has the potential to have untoward effects on the heart. Therefore, the purpose of this study was to evaluate the effects of short‐term consumption of the KD on cardiac mitochondrial function. A secondary objective was to evaluate potential sex differences in response to the KD. Male (n=9) and female (n=11) mice at four‐months of age were randomly assigned to a standard chow or KD (90% fat, 9% protein, 1% carbohydrates) group for 6 weeks. Body weight (BW) was obtained weekly. Glucose and ketone bodies were measured at the end of the dietary intervention via hand‐held meters. After 6 weeks, mitochondria were isolated from all hearts and respiration was assessed with an oxygen electrode system. During the first week, Male‐KD lost 2.5±1.5% of initial BW compared to an increase of 0.3±1.5% of initial BW for Male‐Chow. By the third week, both Male‐KD and Male‐Chow gained BW at a similar rate until the end of the study. In contrast, Female‐KD mice gained BW throughout the 6 weeks and the relative increased compared to baseline was approximately 1.7‐2.0‐fold greater than Female‐chow. Serum ketone bodies were significantly increased in both Male‐KD and Female‐KD mice compared to chow fed groups (Male‐chow, 0.33±0.05 vs. Male‐KD, 0.66±0.10 mM, P<0.05; Female‐chow, 0.33±0.02 vs. Female‐KD, 0.66±0.11 mM, P<0.05). There were no significant sex differences in serum ketone bodies or glucose. State 3 respiration with succinate + ADP was ~35% lower in both male and female KD groups (Male‐chow, 236±14 vs. Male‐KD, 148±11 nmol/min/mg, P<0.05; Female‐chow, 186±22 vs. Female‐KD, 133±10 nmol/min/mg, P=0.08). State 3 respiration with pyruvate/malate + ADP were ~30% lower in both Male and female KD groups (Male‐chow, 157±18 vs. Male‐KD, 105±10 nmol/min/mg, P=NS; Female‐chow, 138±22 vs. Female‐KD, 81±8 nmol/min/mg, P=0.06). No statistically significant sex differences in mitochondria function were noted. In summary, 6‐weeks of KD results in sex differences in patterns of weight gain as male mice experience a transient weight loss and females gain weight throughout the study period. Despite the difference in weight gain, hearts from both males and females fed the KD have similar decrements in mitochondrial function. In conclusion, these findings suggest that the KD may negatively affect cardiac mitochondria and caution against the short‐term use of KD.