Preexercise High-Fat Meal Following Carbohydrate Loading Attenuates Glycogen Utilization During Endurance Exercise in Male Recreational Runners.

ABSTRACT: Iwayama, K, Tanabe, Y, Yajima, K, Tanji, F, Onishi, T, and Takahashi, H. Preexercise high-fat meal following carbohydrate loading attenuates glycogen utilization during endurance exercise in male recreational runners. J Strength Cond Res 37(3): 661-668, 2023-This study aimed to investigate whether one preexercise high-fat meal can increase glycogen conservation during endurance exercise, as compared with one preexercise high-carbohydrate meal. Ten young male recreational runners (22.0 ± 0.6 years; 171.3 ± 0.9 cm; 58.3 ± 1.9 kg; maximal oxygen uptake [V̇ o2 max], 62.0 ± 1.6 ml·kg -1 ·min -1 ) completed 2 exercise trials after high-carbohydrate loading: eating a high-carbohydrate (CHO; 7% protein, 13% fat, 80% carbohydrate) meal or eating a high-fat (FAT; 7% protein, 42% fat, 52% carbohydrate) meal 3.5 hours before exercise. The order of the 2 trials was randomized, and the interval between trials was at least 1 week. The experimental exercise consisted of running on a treadmill for 60 minutes at 95% of each subject's lactate threshold. Muscle and liver glycogen content were assessed using noninvasive carbon magnetic resonance spectroscopy before the experimental meal as well as before and after exercise; respiratory gases were measured continuously during exercise. The respiratory exchange ratio during exercise was statistically lower in the FAT trial than in the CHO trial ( p < 0.01). In addition, muscle ( p < 0.05) and liver ( p < 0.05) glycogen utilization during exercise was less in the FAT trial than in the CHO trial. Therefore, one high-fat meal following carbohydrate loading reduced muscle and liver glycogen use during the 60-minute exercise. These results suggest that this dietary approach may be applied as a strategy to optimize energy utilization during endurance exercise.

Diurnal variation in the glycogen content of the human liver using 13 C MRS.

Glycogen in tissues functions not only as carbohydrate reserves, but also as molecular sensors capable of activating signaling pathways in response to physical activity. While glycogen in the skeletal muscles is mainly a local energy substrate, glycogen in the liver serves as a glucose reserve to maintain normal blood glucose levels in the body, even during the sleep state. The aim of this study is to compare the diurnal variation of glycogen in the muscle and liver of human subjects under normal conditions. The glycogen content was measured in the muscle and liver of 10 young, healthy, male volunteers using 13 C MRS, a non-invasive technique. The subjects remained sedentary, and glycogen concentration was measured six times daily. Experimental meals were provided to achieve individual energy balance, estimated according to the energy requirement guideline for patients from Japan. The largest variation in muscle glycogen compared with 1 h after supper (20:00 on Day 1) was 3.1 ± 8.2 mmol/L (16:00 on Day 2). In the liver, however, the glycogen content decreased by 80.6 ± 40.4 mmol/L through the overnight fasting period (07:00 on Day 2). This study demonstrated that the glycogen content in the liver was significantly lower in the morning, while the glycogen content in the calf muscles underwent minimal diurnal variation. The overnight fast is a characteristic daily condition, in which liver glycogen content is low, whereas muscle glycogen content is relatively unaffected.

Anagliptin increases insulin-induced skeletal muscle glucose uptake via an NO-dependent mechanism in mice.

AIMS/HYPOTHESIS: Recently, incretin-related agents have been reported to attenuate insulin resistance in animal models, although the underlying mechanisms remain unclear. In this study, we investigated whether anagliptin, the dipeptidyl peptidase 4 (DPP-4) inhibitor, attenuates skeletal muscle insulin resistance through endothelial nitric oxide synthase (eNOS) activation in the endothelial cells. We used endothelium-specific Irs2-knockout (ETIrs2KO) mice, which show skeletal muscle insulin resistance resulting from a reduction of insulin-induced skeletal muscle capillary recruitment as a consequence of impaired eNOS activation. METHODS: In vivo, 8-week-old male ETIrs2KO mice were fed regular chow with or without 0.3% (wt/wt) DPP-4 inhibitor for 8 weeks to assess capillary recruitment and glucose uptake by the skeletal muscle. In vitro, human coronary arterial endothelial cells (HCAECs) were used to explore the effect of glucagon-like peptide 1 (GLP-1) on eNOS activity. RESULTS: Treatment with anagliptin ameliorated the impaired insulin-induced increase in capillary blood volume, interstitial insulin concentration and skeletal muscle glucose uptake in ETIrs2KO mice. This improvement in insulin-induced glucose uptake was almost completely abrogated by the GLP-1 receptor (GLP-1R) antagonist exendin-(9-39). Moreover, the increase in capillary blood volume with anagliptin treatment was also completely inhibited by the NOS inhibitor. GLP-1 augmented eNOS phosphorylation in HCAECs, with the effect completely disappearing after exposure to the protein kinase A (PKA) inhibitor H89. These data suggest that anagliptin treatment enhances insulin-induced capillary recruitment and interstitial insulin concentrations, resulting in improved skeletal muscle glucose uptake by directly acting on the endothelial cells via NO- and GLP-1-dependent mechanisms in vivo. CONCLUSIONS/INTERPRETATION: Anagliptin may be a promising agent to ameliorate skeletal muscle insulin resistance in obese patients with type 2 diabetes.

The effect of nocturnal blue light exposure from light-emitting diodes on wakefulness and energy metabolism the following morning.

OBJECTIVES: The control of sleep/wakefulness is associated with the regulation of energy metabolism. The present experiment was designed to assess the effect of nocturnal blue light exposure on the control of sleep/wakefulness and energy metabolism until next noon. METHODS: In a balanced cross-over design, nine young male subjects sitting in a room-size metabolic chamber were exposed either to blue LEDs or to no light for 2 h in the evening. Wavelength of monochromatic LEDs was 465 nm and its intensity was 12.1 µW/cm(2). RESULTS: During sleep, sleep architecture and alpha and delta power of EEG were similar in the two experimental conditions. However, the following morning, when subjects were instructed to stay awake in a sitting position, duration judged as sleep at stages 1 and 2 was longer for subjects who received than for those who received no light exposure. Energy metabolism during sleep was not affected by evening blue light exposure, but the next morning energy expenditure, oxygen consumption, carbon dioxide production and the thermic effect of breakfast were significantly lower in subjects who received blue light exposure than in those who received no light exposure. CONCLUSIONS: Exposure to low intensity blue light in the evening, which does not affect sleep architecture and energy metabolism during sleep, elicits drowsiness and suppression of energy metabolism the following morning.

Comparison of energy requirement estimation using activity record or accelerometer with doubly labeled water method in collegiate male sprinters.

BACKGROUND & AIMS: Track and field sprinters must obtain an optimal body composition to improve sprint performance. To successfully change body composition, it is important to evaluate the estimated energy requirements (EER) and fluctuations in total energy expenditure (TEE). However, methods to accurately evaluate the EER and TEE in sprinters have not been fully investigated. The aim of this study was to compare currently used methods with the doubly labeled water (DLW) method, which is currently the gold standard for evaluating EER and TEE. METHODS: Ten male collegiate sprinters participated in the study. We evaluated TEEDLW and compared it with the EER calculated using two equations used by the National Institute of Health and Nutrition (NIHN) and the Japan Institute of Sports Sciences (JISS). In addition, we evaluated the TEE from the activity record (AR) and triaxial accelerometer (ACC). RESULTS: TEEDLW (3172 ± 415 kcal/day) was not significantly different from EERNIHN (p = 0.076) or EERJISS (p = 0.967). In addition, there were no significant differences between TEEDLW and TEEAR (p = 0.218). However, two accelerometer-derived equations used to evaluate TEE were found to have underestimated (2783 ± 377 kcal/day, p < 0.001) and overestimated (3405 ± 369 kcal/day, p = 0.009) the TEE. CONCLUSION: Our results suggest that EERNIHN and EERJISS may be useful in evaluating the EER of collegiate male sprinters on a group basis, and AR may be more accurate than ACC in evaluating the TEE. These results may be helpful when considering nutritional support for male collegiate sprinters.

Exercise Timing Matters for Glycogen Metabolism and Accumulated Fat Oxidation over 24 h.

Due to increasingly diverse lifestyles, exercise timings vary between individuals: before breakfast, in the afternoon, or in the evening. The endocrine and autonomic nervous systems, which are associated with metabolic responses to exercise, show diurnal variations. Moreover, physiological responses to exercise differ depending on the timing of the exercise. The postabsorptive state is associated with greater fat oxidation during exercise compared to the postprandial state. The increase in energy expenditure persists during the post-exercise period, known as "Excess Post-exercise Oxygen Consumption". A 24 h evaluation of accumulated energy expenditure and substrate oxidation is required to discuss the role of exercise in weight control. Using a whole-room indirect calorimeter, researchers revealed that exercise performed during the postabsorptive state, but not during the postprandial state, increased accumulated fat oxidation over 24 h. The time course of the carbohydrate pool, as estimated by indirect calorimetry, suggests that glycogen depletion after postabsorptive exercise underlies an increase in accumulated fat oxidation over 24 h. Subsequent studies using 13C magnetic resonance spectroscopy confirmed that the variations in muscle and liver glycogen caused by postabsorptive or postprandial exercise were consistent with indirect calorimetry data. These findings suggest that postabsorptive exercise alone effectively increases 24 h fat oxidation.

Diurnal variations in muscle and liver glycogen differ depending on the timing of exercise.

It has been suggested that glycogen functions not only in carbohydrate energy storage, but also as molecular sensors capable of activating lipolysis. This study aimed to compare the variation in liver and muscle glycogen during the day due to different timing of exercise. Nine healthy young men participated in two trials in which they performed a single bout of exercise at 70% of their individual maximal oxygen uptake for 60 min in the post-absorptive (morning) or post-prandial (afternoon) state. Liver and muscles glycogen levels were measured using carbon magnetic resonance spectroscopy (13C MRS). Diurnal variations in liver and muscle glycogen compared to baseline levels were significantly different depending on the timing of exercise. The effect of the timing of exercise on glycogen fluctuation is known to be related to a variety of metabolic signals, and the results of this study will be useful for future research on energy metabolism.

Metabolic flexibility during sleep.

Known as metabolic flexibility, oxidized substrate is selected in response to changes in the nutritional state. Sleep imposes an extended duration of fasting, and oxidized substrates during sleep were assumed to progressively shift from carbohydrate to fat, thereby gradually decreasing the respiratory quotient (RQ). Contrary to this assumption, whole-room indirect calorimetry with improved time resolution revealed that RQ re-ascended prior to awakening, and nadir of RQ in non-obese young adults occurred earlier in women than men after bedtime. The transient decrease in RQ during sleep was blunted in metabolically inflexible men with smaller amplitude of diurnal rhythm in RQ. Similarly, the effect of 10 years difference in age on RQ became significant during sleep; the decrease in RQ during sleep was blunted in older subjects. Inter-individual difference in RQ become apparent during sleep, and it might serve as a window to gain insight into the early-stage pathogenesis of metabolic inflexibility.

Exercise improves the quality of slow-wave sleep by increasing slow-wave stability.

Exercise can improve sleep by reducing sleep latency and increasing slow-wave sleep (SWS). Some studies, however, report adverse effects of exercise on sleep architecture, possibly due to a wide variety of experimental conditions used. We examined the effect of exercise on quality of sleep using standardized exercise parameters and novel analytical methods. In a cross-over intervention study we examined the effect of 60 min of vigorous exercise at 60% [Formula: see text]max on the metabolic state, assessed by core body temperature and indirect calorimetry, and on sleep quality during subsequent sleep, assessed by self-reported quality of sleep and polysomnography. In a novel approach, envelope analysis was performed to assess SWS stability. Exercise increased energy expenditure throughout the following sleep phase. The subjective assessment of sleep quality was not improved by exercise. Polysomnography revealed a shorter rapid eye movement latency and reduced time spent in SWS. Detailed analysis of the sleep electro-encephalogram showed significantly increased delta power in SWS (N3) together with increased SWS stability in early sleep phases, based on delta wave envelope analysis. Although vigorous exercise does not lead to a subjective improvement in sleep quality, sleep function is improved on the basis of its effect on objective EEG parameters.

Muscle Glycogen Content during Endurance Training under Low Energy Availability.

PURPOSE: The present study investigated the effects of three consecutive days of endurance training under conditions of low energy availability (LEA) on the muscle glycogen content, muscle damage markers, endocrine regulation, and endurance capacity in male runners. METHODS: Seven male long-distance runners (19.9 ± 1.1 yr, 175.6 ± 4.7 cm, 61.4 ± 5.3 kg, maximal oxygen uptake [V˙O2max]: 67.5 ± 4.3 mL·kg·min) completed two trials consisting of three consecutive days of endurance training under LEA (18.9 ± 1.9 kcal·kg FFM·d) or normal energy availability (NEA) (52.9 ± 5.0 kcal·kg FFM·d). The order of the two trials was randomized, with a 2-wk interval between trials. The endurance training consisted of 75 min of treadmill running at 70% of V˙O2max. Muscle glycogen content, respiratory gas variables, and blood and urine variables were measured in the morning for three consecutive days of training (days 1-3) and on the following morning after training (day 4). As an indication of endurance capacity, time to exhaustion at 19.0 ± 0.8 km·h to elicit 90% of V˙O2max was evaluated on day 4. RESULTS: During the training period, body weight, fat-free mass, and skeletal muscle volume were significantly reduced in LEA (P = 0.02 for body weight and skeletal muscle volume, P = 0.01 for fat-free mass). Additionally, muscle glycogen content was significantly reduced in LEA (~30%, P < 0.001), with significantly lower values than those in NEA (P < 0.001). Time to exhaustion was not significantly different between the two trials (~20 min, P = 0.39). CONCLUSIONS: Three consecutive days of endurance training under LEA decreased muscle glycogen content with lowered body weight. However, endurance capacity was not significantly impaired.

Effect of low energy availability during three consecutive days of endurance training on iron metabolism in male long distance runners.

We investigated the effect of low energy availability (LEA) during three consecutive days of endurance training on muscle glycogen content and iron metabolism. Six male long distance runners completed three consecutive days of endurance training under LEA or neutral energy availability (NEA) conditions. Energy availability was set at 20 kcal/kg fat-free mass (FFM)/day for LEA and 45 kcal/kg FFM/day for NEA. The subjects ran for 75 min at 70% of maximal oxygen uptake ( V˙ O2max ) on days 1-3. Venous blood samples were collected following an overnight fast on days 1-4, immediately and 3 hr after exercise on day 3. The muscle glycogen content on days 1-4 was evaluated by carbon-magnetic resonance spectroscopy. In LEA condition, the body weight and muscle glycogen content on days 2-4, and the FFM on days 2 and 4 were significantly lower than those on day1 (p < .05 vs. day1), whereas no significant change was observed throughout the training period in NEA condition. On day 3, muscle glycogen content before exercise was negatively correlated with serum iron level (immediately after exercise, 3 hr after exercise), serum hepcidin level immediately after exercise, and plasma IL-6 level immediately after exercise (p < .05). Moreover, serum hepcidin level on day 4 was significantly higher in LEA condition than that in NEA condition (p < .05). In conclusion, three consecutive days of endurance training under LEA reduced the muscle glycogen content with concomitant increased serum hepcidin levels in male long distance runners.

Effect of skipping breakfast for 6 days on energy metabolism and diurnal rhythm of blood glucose in young healthy Japanese males.

BACKGROUND: Skipping breakfast has become a common trend that may lead to obesity and type 2 diabetes. Previous studies, which imposed a single incidence of breakfast skipping, did not observe any decrease in 24-h energy expenditure. Furthermore, the effects of breakfast skipping on diurnal blood glucose profiles over 24 h are contradictory. OBJECTIVE: The aim of this study was to clarify the influence of 6 consecutive days of breakfast skipping and sedentary behavior on energy metabolism and glycemic control. METHODS: Ten young men participated in 2 trials (with or without breakfast) that lasted for 6 consecutive days, and the 2 trials were conducted 1 wk apart with a repeated-measures design. During the meal intervention, each subject's blood glucose was measured using the continuous glucose monitoring system. If breakfast was skipped, subjects ate large meals at lunch and dinner such that the 24-h energy intake was identical to that of the 3-meal condition. At 2200 on the fifth day, the subjects entered a room-sized respiratory chamber, where they remained for 33 h, and were instructed to carry out sedentary behavior. RESULTS: The glucose levels were similar between the 2 meal conditions during the first 5 d of meal intervention, but the blood glucose at 2300 was higher in the breakfast-skipping condition than in the 3-meal condition. Breakfast skipping elevated postprandial glycemic response after lunch on the first day of meal intervention. On the sixth day, there were no significant differences in 24-h energy expenditure and substrate oxidation. When subjects remained in a metabolic chamber, the level of physical activity significantly decreased, glycemic stability slightly deteriorated, and mean blood glucose over 24 h was higher in the breakfast-skipping trial than in the 3-meal trial. CONCLUSIONS: Sedentary lifestyle and repeated breakfast skipping caused abnormal glucose fluctuations, whereas 24-h energy metabolism remained unaffected. Clinical Trial Registry: This trial was registered at http://www.umin.ac.jp/english/ as UMIN000032346.

Hepatic Sdf2l1 controls feeding-induced ER stress and regulates metabolism.

Dynamic metabolic changes occur in the liver during the transition between fasting and feeding. Here we show that transient ER stress responses in the liver following feeding terminated by Sdf2l1 are essential for normal glucose and lipid homeostasis. Sdf2l1 regulates ERAD through interaction with a trafficking protein, TMED10. Suppression of Sdf2l1 expression in the liver results in insulin resistance and increases triglyceride content with sustained ER stress. In obese and diabetic mice, Sdf2l1 is downregulated due to decreased levels of nuclear XBP-1s, whereas restoration of Sdf2l1 expression ameliorates glucose intolerance and fatty liver with decreased ER stress. In diabetic patients, insufficient induction of Sdf2l1 correlates with progression of insulin resistance and steatohepatitis. Therefore, failure to build an ER stress response in the liver may be a causal factor in obesity-related diabetes and nonalcoholic steatohepatitis, for which Sdf2l1 could serve as a therapeutic target and sensitive biomarker.

Meal rich in rapeseed oil increases 24-h fat oxidation more than meal rich in palm oil.

The fatty acid composition of the diet has been linked to the prevalence of diabetes and cardiovascular diseases. Compared with monounsaturated fatty acids, saturated fatty acids decrease fat oxidation and diet-induced thermogenesis. A potential limitation of previous studies was the short duration (≦5h) of calorimetry used. The present study compared the effects of a meal rich in saturated and unsaturated fatty acids on 24-h of fat oxidation. Ten males participated in two sessions of indirect calorimetry in a whole-room metabolic chamber. At each session, subjects consumed three meals rich in palm oil (44.3% as saturated, 42.3% as monounsaturated and 13.4% as polyunsaturated fatty acid) or rapeseed oil (11.7% as saturated, 59.3% as monounsaturated and 29.0% as polyunsaturated fatty acid). Fat oxidation over 24-h was significantly higher in the meal rich in rapeseed oil (779 ± 202 kcal/day) than that rich in palm oil (703 ± 158 kcal/day, P < 0.05), although energy expenditure was similar between both meal conditions. Meal rich in unsaturated fatty acids increased the oxidation of exogenous and/or endogenous fat. The results of a long calorimetry period indicate that rapeseed oil offered an advantage toward increased 24-h fat oxidation in healthy young males.

Downregulation of macrophage Irs2 by hyperinsulinemia impairs IL-4-indeuced M2a-subtype macrophage activation in obesity.

M2a-subtype macrophage activation is known to be impaired in obesity, although the underlying mechanisms remain poorly understood. Herein, we demonstrate that, the IL-4/Irs2/Akt pathway is selectively impaired, along with decreased macrophage Irs2 expression, although IL-4/STAT6 pathway is maintained. Indeed, myeloid cell-specific Irs2-deficient mice show impairment of IL-4-induced M2a-subtype macrophage activation, as a result of stabilization of the FoxO1/HDAC3/NCoR1 corepressor complex, resulting in insulin resistance under the HF diet condition. Moreover, the reduction of macrophage Irs2 expression is mediated by hyperinsulinemia via the insulin receptor (IR). In myeloid cell-specific IR-deficient mice, the IL-4/Irs2 pathway is preserved in the macrophages, which results in a reduced degree of insulin resistance, because of the lack of IR-mediated downregulation of Irs2. We conclude that downregulation of Irs2 in macrophages caused by hyperinsulinemia is responsible for systemic insulin resistance via impairment of M2a-subtype macrophage activation in obesity.

Energy metabolism differs between sleep stages and begins to increase prior to awakening.

PURPOSE: Human sleep is generally consolidated into a single prolonged period, and its metabolic consequence is to impose an extended period of fasting. Changes in sleep stage and homeostatic sleep drive following sleep onset may affect sleeping metabolic rate through cross talk between the mechanisms controlling energy metabolism and sleep. The purpose of this study was to isolate the effects of sleep stage and time after sleep onset on sleeping metabolic rate. METHODS: The sleeping metabolic rate of 29 healthy adults was measured using whole room indirect calorimetry, during which polysomnographic recording of sleep was performed. The effects of sleep stage and time after sleep onset on sleeping metabolic rate were evaluated using a semi-parametric regression analysis. A parametric analysis was used for the effect of sleep stage and a non-parametric analysis was used for the effect of time. RESULTS: Energy expenditure differed significantly between sleep stages: wake after sleep onset (WASO)>stage 2, slow wave sleep (SWS), and REM; stage 1>stage 2 and SWS; and REM>SWS. Similarly, carbohydrate oxidation differed significantly between sleep stages: WASO > stage 2 and SWS; and stage 1>SWS. Energy expenditure and carbohydrate oxidation decreased during the first half of sleep followed by an increase during the second half of sleep. CONCLUSIONS: This study identified characteristic phenotypes in energy expenditure and carbohydrate oxidation indicating that sleeping metabolic rate differs between sleep stages.

Exercise before breakfast increases 24-h fat oxidation in female subjects.

BACKGROUND: Exercise performed in a postprandial state does not increase 24-h fat oxidation of male and female subjects. Conversely, it has been shown in male subjects that exercise performed in a postabsorptive state increases 24-h fat oxidation compared with that in sedentary control and that with exercise trials performed after breakfast, lunch, or dinner. There is a paucity of study evaluating the effect of exercise performed in a postabsorptive state in female subjects. METHOD: Nine young female subjects participated in indirect calorimetry measurement over 24-h using a room-size metabolic chamber in which subjects remained sedentary or performed 60 min exercise before breakfast at 50% of [Formula: see text]. Exercise was accompanied by an increase in energy intake to ensure that subjects were in a similar state of energy balance over 24 h for the two trials. FINDINGS: Compared with the sedentary condition, exercise performed before breakfast increased 24-h fat oxidation (519 ± 37 vs. 400 ± 41 kcal/day). Time courses of relative energy balance differed between trials with transient negative energy balance observed before breakfast. The lowest values of relative energy balance observed during the 24-h calorimetry, i.e., transient energy deficit, were greater in exercise trials than in sedentary trials. The transient deficit in carbohydrate balance was also observed before breakfast, and magnitude of the deficit was greater in exercise trial compared to that of sedentary trial. INTERPRETATION: Under energy-balanced conditions, exercise performed in a post-absorptive state increases 24-h fat oxidation in female subjects. The effect of exercise performed before breakfast can be attributed to nutritional state: a transient deficit in energy and carbohydrate at the end of exercise.

Deficiency of the hepatokine selenoprotein P increases responsiveness to exercise in mice through upregulation of reactive oxygen species and AMP-activated protein kinase in muscle.

Exercise has numerous health-promoting effects in humans; however, individual responsiveness to exercise with regard to endurance or metabolic health differs markedly. This 'exercise resistance' is considered to be congenital, with no evident acquired causative factors. Here we show that the anti-oxidative hepatokine selenoprotein P (SeP) causes exercise resistance through its muscle receptor low-density lipoprotein receptor-related protein 1 (LRP1). SeP-deficient mice showed a 'super-endurance' phenotype after exercise training, as well as enhanced reactive oxygen species (ROS) production, AMP-activated protein kinase (AMPK) phosphorylation and peroxisome proliferative activated receptor γ coactivator (Ppargc)-1α (also known as PGC-1α; encoded by Ppargc1a) expression in skeletal muscle. Supplementation with the anti-oxidant N-acetylcysteine (NAC) reduced ROS production and the endurance capacity in SeP-deficient mice. SeP treatment impaired hydrogen-peroxide-induced adaptations through LRP1 in cultured myotubes and suppressed exercise-induced AMPK phosphorylation and Ppargc1a gene expression in mouse skeletal muscle-effects which were blunted in mice with a muscle-specific LRP1 deficiency. Furthermore, we found that increased amounts of circulating SeP predicted the ineffectiveness of training on endurance capacity in humans. Our study suggests that inhibitors of the SeP-LRP1 axis may function as exercise-enhancing drugs to treat diseases associated with a sedentary lifestyle.

Tofogliflozin Improves Insulin Resistance in Skeletal Muscle and Accelerates Lipolysis in Adipose Tissue in Male Mice.

Sodium glucose cotransporter 2 inhibitors have attracted attention as they exert antidiabetic and antiobesity effects. In this study, we investigated the effects of tofogliflozin on glucose homeostasis and its metabolic consequences and clarified the underlying molecular mechanisms. C57BL/6 mice were fed normal chow containing tofogliflozin (0.005%) for 20 weeks or a high-fat diet containing tofogliflozin (0.005%) for 8 weeks ad libitum. In addition, the animals were pair-fed in relation to controls to exclude the influence of increased food intake. Tofogliflozin reduced the body weight gain, mainly because of fat mass reduction associated with a diminished adipocyte size. Glucose tolerance and insulin sensitivity were ameliorated. The serum levels of nonesterified fatty acid and ketone bodies were increased and the respiratory quotient was decreased in the tofogliflozin-treated mice, suggesting the acceleration of lipolysis in the white adipose tissue and hepatic ß-oxidation. In fact, the phosphorylation of hormone-sensitive lipase and the adipose triglyceride lipase protein levels in the white adipose tissue as well as the gene expressions related to ß-oxidation, such as Cpt1α in the liver, were significantly increased. The hepatic triglyceride contents and the expression levels of lipogenic genes were decreased. Pair-fed mice exhibited almost the same results as mice fed an high-fat diet ad libitum. Moreover, a hyperinsulinemic-euglycemic clamp revealed that tofogliflozin improved insulin resistance by increasing glucose uptake, especially in the skeletal muscle, in pair-fed mice. Taken together, these results suggest tofogliflozin ameliorates insulin resistance and obesity by increasing glucose uptake in skeletal muscle and lipolysis in adipose tissue.