Vitamin D supplementation associated with physical exercise promotes a tolerogenic immune environment without effect on mammary tumour growth in C57BL/6 mice.

PURPOSE: High plasma vitamin D (VitD) level and regular exercise (Ex) are known to have anti-cancer and immunomodulatory effects. This study aimed to evaluate the impact of VitD supplementation and imposed physical Ex on mammary tumour growth and immune response in ovariectomised mice fed high-fat (HF) diet. METHODS: Ovariectomised 33-week-old mice C57BL/6 (n = 60), housed in enriched environment (EE), were fed HF diet (450 kcal/100 g) supplemented or not with VitD (HF/HF + D: 125/1225 IU/100 g) for 12 weeks and submitted or not to Ex (HF + Ex; HF + D + Ex) on treadmill (45 min/day, 5 days/week). At w8, syngeneic tumour cells EO771 were orthotopically injected into the 4th mammary gland. Spontaneous activity (SPA), maximal speed (MS) and forelimb grip strength (GS) were measured. Tumour immune cells infiltrate was phenotyped by FACS. Data (mean ± SEM) were analysed by two-way ANOVA + Tukey post-test. RESULTS: Ex (p = 0.01) and VitD (p = 0.05) reduced body weight gain. Exercise decreased visceral fat mass [g: 1.5 ± 0.8 (HF); 1.2 ± 0.65 (HF + Ex); 0.9 ± 0.6 (HF + D + Ex); p = 0.03]. SPA (p < 0.0001) and GS (p = 0.01) were higher in HF + D + Ex mice vs others. No effect of Ex or VitD on tumour growth was detected. In tumour, VitD decreased the proportion of NK (p = 0.03), while Ex increased it (p = 0.03). The Th1/Th2 ratio is lowered by VitD (p = 0.05), while Tc/Treg ratio was not affected either by Exercise or VitD. CONCLUSION: In our experimental conditions, VitD supplementation and physical exercise have synergetic effects reducing the weight gain under HF diet and improving the physical capacities of mice. VitD coupled with exercise induces an immunosuppressive response without effect on tumour growth.

A new leptin-mediated mechanism for stimulating fatty acid oxidation: a pivotal role for sarcolemmal FAT/CD36.

Leptin stimulates fatty acid oxidation in muscle and heart; but, the mechanism by which these tissues provide additional intracellular fatty acids for their oxidation remains unknown. We examined, in isolated muscle and cardiac myocytes, whether leptin, via AMP-activated protein kinase (AMPK) activation, stimulated fatty acid translocase (FAT/CD36)-mediated fatty acid uptake to enhance fatty acid oxidation. In both mouse skeletal muscle and rat cardiomyocytes, leptin increased fatty acid oxidation, an effect that was blocked when AMPK phosphorylation was inhibited by adenine 9-ß-d-arabinofuranoside or Compound C. In wild-type mice, leptin induced the translocation of FAT/CD36 to the plasma membrane and increased fatty acid uptake into giant sarcolemmal vesicles and into cardiomyocytes. In muscles of FAT/CD36-KO mice, and in cardiomyocytes in which cell surface FAT/CD36 action was blocked by sulfo-N-succinimidyl oleate, the leptin-stimulated influx of fatty acids was inhibited; concomitantly, the normal leptin-stimulated increase in fatty acid oxidation was also prevented, despite the normal leptin-induced increase in AMPK phosphorylation. Conversely, in muscle of AMPK kinase-dead mice, leptin failed to induce the translocation of FAT/CD36, along with a failure to stimulate fatty acid uptake and oxidation. Similarly, when siRNA was used to reduce AMPK in HL-1 cardiomyocytes, leptin failed to induce the translocation of FAT/CD36. Our studies have revealed a novel mechanism of leptin-induced fatty acid oxidation in muscle tissue; namely, this process is dependent on the activation of AMPK to induce the translocation of FAT/CD36 to the plasma membrane, thereby stimulating fatty acid uptake. Without increasing this leptin-stimulated, FAT/CD36-dependent fatty acid uptake process, leptin-stimulated AMPK phosphorylation does not enhance fatty acid oxidation.

Resveratrol prevents the wasting disorders of mechanical unloading by acting as a physical exercise mimetic in the rat.

Long-term spaceflight induces hypokinesia and hypodynamia, which, along microgravity per se, result in a number of significant physiological alterations, such as muscle atrophy, force reduction, insulin resistance, substrate use shift from fats to carbohydrates, and bone loss. Each of these adaptations could turn to serious health deterioration during the long-term spaceflight needed for planetary exploration. We hypothesized that resveratrol (RES), a natural polyphenol, could be used as a nutritional countermeasure to prevent muscle metabolic and bone adaptations to 15 d of rat hindlimb unloading. RES treatment maintained a net protein balance, soleus muscle mass, and soleus muscle maximal force contraction. RES also fully maintained soleus mitochondrial capacity to oxidize palmitoyl-carnitine and reversed the decrease of the glutathione vs. glutathione disulfide ratio, a biomarker of oxidative stress. At the molecular level, the protein content of Sirt-1 and COXIV in soleus muscle was also preserved. RES further protected whole-body insulin sensitivity and lipid trafficking and oxidation, and this was likely associated with the maintained expression of FAT/CD36, CPT-1, and peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) in muscle. Finally, chronic RES supplementation maintained the bone mineral density and strength of the femur. For the first time, we report a simple countermeasure that prevents the deleterious adaptations of the major physiological functions affected by mechanical unloading. RES could thus be envisaged as a nutritional countermeasure for spaceflight but remains to be tested in humans.

Nitrate consumption preserves HFD-induced skeletal muscle mitochondrial ADP sensitivity and lysine acetylation: A potential role for SIRT1.

Dietary nitrate supplementation, and the subsequent serial reduction to nitric oxide, has been shown to improve glucose homeostasis in several pre-clinical models of obesity and insulin resistance. While the mechanisms remain poorly defined, the beneficial effects of nitrate appear to be partially dependent on AMPK-mediated signaling events, a central regulator of metabolism and mitochondrial bioenergetics. Since AMPK can activate SIRT1, we aimed to determine if nitrate supplementation (4 mM sodium nitrate via drinking water) improved skeletal muscle mitochondrial bioenergetics and acetylation status in mice fed a high-fat diet (HFD: 60% fat). Consumption of HFD induced whole-body glucose intolerance, and within muscle attenuated insulin-induced Akt phosphorylation, mitochondrial ADP sensitivity (higher apparent Km), submaximal ADP-supported respiration, mitochondrial hydrogen peroxide (mtH2O2) production in the presence of ADP and increased cellular protein carbonylation alongside mitochondrial-specific acetylation. Consumption of nitrate partially preserved glucose tolerance and, within skeletal muscle, normalized insulin-induced Akt phosphorylation, mitochondrial ADP sensitivity, mtH2O2, protein carbonylation and global mitochondrial acetylation status. Nitrate also prevented the HFD-mediated reduction in SIRT1 protein, and interestingly, the positive effects of nitrate ingestion on glucose homeostasis and mitochondrial acetylation levels were abolished in SIRT1 inducible knock-out mice, suggesting SIRT1 is required for the beneficial effects of dietary nitrate. Altogether, dietary nitrate preserves mitochondrial ADP sensitivity and global lysine acetylation in HFD-fed mice, while in the absence of SIRT1, the effects of nitrate on glucose tolerance and mitochondrial acetylation were abrogated.

Effect of prior treatment with resveratrol on density and structure of rat long bones under tail-suspension.

Physical inactivity during space flight or prolonged bed rest causes rapid and marked loss of bone mass in humans. Resveratrol, a red wine polyphenol that is currently under study for its therapeutic antioxidant properties, has been shown to significantly modulate biomarkers of bone metabolism, i.e., to promote osteoblast differentiation and to prevent bone loss induced by estrogen deficiency. However, there is no direct evidence supporting its inhibitory effect toward bone loss during physical inactivity. In the present study, effects of resveratrol on bone mineral density (BMD), bone mineral content, and bone structure were examined in the femora and tibiae of tail-suspended and unsuspended rats using X-ray micro-computed tomography (micro-CT). Rats were treated with 400 mg/kg/day of resveratrol for 45 days and half of them were suspended during the last 2 weeks of treatment. Suspension caused a decrease in tibial and femoral BMD and deterioration of trabecular and cortical bone. Bone deterioration during suspension was paralleled by increased bone marrow area, which could be caused by an increase in stromal cells with osteoclastogenic potential or in adipocytes. Resveratrol had a preventive effect against bone loss induced by hindlimb immobilization. In particular, trabecular bone in the proximal tibial metaphysis was totally preserved in rats treated with resveratrol before tail-suspension.

Dietary palmitate and linoleate oxidations, oxidative stress, and DNA damage differ according to season in mouse lemurs exposed to a chronic food deprivation.

This study investigated the extent to which the increase in torpor expression in the grey mouse lemur, due to graded food restriction, is modulated by a trade-off between a whole body sparing of polyunsaturated dietary fatty acids and the related oxidative stress generated during daily torpor. We measured changes in torpor frequency, total energy expenditure (TEE), linoleate (polyunsaturated fatty acid) and palmitate (saturated fatty acid) oxidation, hexanoyl-lysine (HEL; the product of linoleate peroxidation), and 8-hydroxydeoxyguanosine (8OHdG; a marker of DNA damage). Animals under summer-acclimated long days (LD) or winter-acclimated short days (SD) were exposed to a 40% (LD40 and SD40) and 80% (LD80 and SD80) 35-day calorie restriction (CR). During CR, all groups reduced their body mass, but LD80 animals reached survival-threatened levels at day 22 and were then excluded from the CR trial. Only SD mouse lemurs increased their torpor frequency with CR and displayed a decrease in their TEE adjusted for fat-free mass. After CR, SD40 mouse lemurs shifted the dietary fatty acid oxidation toward palmitate and spared linoleate. Such a shift was not observed in LD animals and during severe CR, during which oxidation of both dietary fatty acids was increased. Concomitantly, HEL increased in both LD40 and SD80 groups, whereas DNA damage was only seen in SD80 food-restricted animals. HEL correlated positively with linoleate oxidation confirming in vivo the substrate/product relationship demonstrated in vitro, and negatively with TEE adjusted for fat-free mass, suggesting higher oxidative stress associated with increased torpor expression. This suggests a seasonal-dependant, cost-benefit trade-off between maximizing torpor propensity and minimizing oxidative stress that is associated with a shift toward sparing of dietary polyunsaturated fatty acids that is dependent upon the expression of a winter phenotype.

Lung Stereotactic Arc Therapy in Mice: Development of Radiation Pneumopathy and Influence of HIF-1α Endothelial Deletion.

PURPOSE: Stereotactic body radiation therapy offers good lung local tumor control by the administration of a high dose per fraction in small volumes. Stereotactic body radiation therapy preclinical modeling is now possible, and our aim was to develop a model of focal irradiation of the mouse lung and to investigate the impact of conditional hypoxia-inducible factor 1α (HIF-1α) deletion in the endothelium on radiation-induced tissue damage. METHODS AND MATERIALS: The Small Animal Radiation Research Platform was used to create a mouse model of focal irradiation of the lung using arc therapy. HIF-1α conditional deletion was obtained by crossing mice expressing Cre recombinase under the endothelial promoter VE-cadherin (VECad-Cre+/+ mice) with HIF-1α floxed mice. RESULTS: Lung stereotactic arc therapy allows thoracic wall sparing and long-term studies. However, isodose curves showed that neighboring organs received significant doses of radiation, as revealed by ipsilateral lung acute red hepatization and major gene expression level modifications. Conditional HIF-1α deletion reduced acute lung edema and tended to diminish neutrophil infiltrate, but it had no impact on long-term global tissue damage. CONCLUSIONS: Arc therapy for focal high-dose irradiation of mouse lung is an efficient model for long-term studies. However, irradiation may have a strong impact on the structure and function of neighboring organs, which must be considered. HIF-1α conditional deletion has no beneficial impact on lung damage in this irradiation schedule.

Acceleration-based training: A new mode of training in senescent rats improving performance and left ventricular and muscle functions.

High intensity training (HIT) has been shown to improve maximal aerobic capacity and muscle protein synthesis but has not yet been investigated in senescent rats. We hypothesized that the change of speed (acceleration) during each bout of HIT acts as a stimulus responsible for the adaptations of the organism to exercise. Twenty two month-old (mo) rats (n=13) were subjected to a short acceleration protocol (20-30min) of exercise, comprising 3 independent bouts of acceleration and compared to an age-matched sedentary group (n=14). The protocol was repeated twice a week for two months. Following the protocol, performance, cardiac function, muscle mechanics, and the cellular and molecular pathways that are implicated in exercise adaptations were investigated. This new training, comprising only 16 sessions, improved maximal oxygen uptake (⩒O2peak; +6.6%, p<0.05), running distance (+95.2%; p<0.001), speed (+29.7%; p<0.01) and muscle function of 24mo rats in only 8weeks. This new training protocol induced cardiac hypertrophy and improved fractional shortening (47.3% vs. 41.1% in the control group, p<0.01) and ejection fraction. Moreover, it also improved the mechanics of skeletal muscle by increasing developed force (+31% vs. the control group, p<0.05) and maximal mechanical efficiency, activated the IGF1/mTOR/Akt pathway, and reduced the Smad2/3 pathway. Our results clearly show that the change in speed is a stimulus to control cardiac and skeletal muscle mass. This acceleration-based training is not time-consuming and may be adaptable for athletes, the elderly or chronic disease patients in order to improve strength, oxidative capacity, and quality of life.

Case Studies in Physiology: Maximal oxygen consumption and performance in a centenarian cyclist.

The purpose of this study was to examine the physiological characteristics of an elite centenarian cyclist who, at 101 yr old, established the 1-h cycling record for individuals ≥100 yr old (24.25 km) and to determine the physiological factors associated with his performance improvement 2 yr later at 103 yr old (26.92 km; +11%). Before each record, he performed an incremental test on a cycling ergometer. For 2 yr, he trained 5,000 km/yr with a polarized training that involved cycling 80% of mileage at "light" rate of perceived exertion (RPE) ≤12 and 20% at "hard" RPE ≥15 at a cadence between 50 and 70 rpm. His body weight and lean body mass did not change, while his maximal oxygen consumption (V̇o2max) increased (31-35 ml·kg-1·min-1; +13%). Peak power output increased from 90 to 125 W (+39%), mainly because of increasing the maximal pedaling frequency (69-90 rpm; +30%). Maximal heart rate did not change (134-137 beats/min) in contrast to the maximal ventilation (57-70 l/min, +23%), increasing with both the respiratory frequency (38-41 cycles/min; +8%) and the tidal volume (1.5-1.7 liters; +13%). Respiratory exchange ratio increased (1.03-1.14) to the same extent as tolerance to V̇co2 In conclusion, it is possible to increase performance and V̇o2max with polarized training focusing on a high pedaling cadence even after turning 100 yr old.NEW & NOTEWORTHY This study shows, for the first time, that maximal oxygen consumption (+13%) and performance (+11%) can still be increased between 101 and 103 yr old with 2 yr of training and that a centenarian is able, at 103 yr old, to cover 26.9 km/h in 1 h.

Arsenite modulates cardiac substrate preference by translocation of GLUT4, but not CD36, independent of mitogen-activated protein kinase signaling.

The protein thiol-modifying agent arsenite, a potent activator of stress signaling, was used to examine the involvement of MAPKs in the regulation of cardiac substrate uptake. Arsenite strongly induced p38 MAPK phosphorylation in isolated rat cardiac myocytes but also moderately enhanced phosphorylation of p42/44 ERK and p70 S6K. At the level of cardiomyocytic substrate use, arsenite enhanced glucose uptake dose dependently up to 5.1-fold but failed to stimulate long-chain fatty acid uptake. At the substrate transporter level, arsenite stimulated the translocation of GLUT4 to the sarcolemma but failed to recruit CD36 or FABPpm. Because arsenite did not influence the intrinsic activity of glucose transporters, GLUT4 translocation is entirely responsible for the selective increase in glucose uptake by arsenite. Moreover, the nonadditivity of arsenite-induced glucose uptake and insulin-induced glucose uptake indicates that arsenite recruits GLUT4 from insulin-responsive intracellular stores. Inhibitor studies with SB203580/SB202190, PD98059, and rapamycin indicate that activation of p38 MAPK, p42/44 ERK, and p70 S6K, respectively, are not involved in arsenite-induced glucose uptake. In addition, all these kinases do not play a role in regulation of cardiac glucose and long-chain fatty acid uptake by insulin. Hence, arsenite's selective stimulation of glucose uptake appears unrelated to its signaling actions, suggesting that arsenite acts via thiol modification of a putative intracellular protein target of arsenite within insulin-responsive GLUT4-containing stores. Because of arsenite's selective stimulation of cardiac glucose uptake, identification of this putative target of arsenite within the GLUT4-storage compartment may indicate whether it is a target for future strategies in prevention of diabetic cardiomyopathy.

Validation of a Ramp Running Protocol for Determination of the True VO2max in Mice.

In the field of comparative physiology, it remains to be established whether the concept of VO2max is valid in the mouse and, if so, how this value can be accurately determined. In humans, VO2max is generally considered to correspond to the plateau observed when VO2 no longer rises with an increase in workload. In contrast, the concept of VO2peak tends to be used in murine studies. The objectives of the present study were to determine whether (i) a continuous ramp protocol yielded a higher VO2peak than a stepwise, incremental protocol, and (ii) the VO2peak measured in the ramp protocol corresponded to VO2max. The three protocols (based on intensity-controlled treadmill running until exhaustion with eight female FVB/N mice) were performed in random order: (a) an incremental protocol that begins at 10 m.min(-1) speed and increases by 3 m.min(-1) every 3 min. (b) a ramp protocol with slow acceleration (3 m.min(-2)), and (c) a ramp protocol with fast acceleration (12 m.min(-2)). Each protocol was performed with two slopes (0 and 25°). Hence, each mouse performed six exercise tests. We found that the value of VO2peak was protocol-dependent (p < 0.05) and was highest (59.0 ml.kg (0.75).min(-1)) for the 3 m.min(-2) 0° ramp protocol. In the latter, the presence of a VO2max plateau was associated with the fulfillment of two secondary criteria (a blood lactate concentration >8 mmol.l(-1) and a respiratory exchange ratio >1). The total duration of the 3 m.min(-2) 0° ramp protocol was shorter than that of the incremental protocol. Taken as a whole, our results suggest that VO2max in the mouse is best determined by applying a ramp exercise protocol with slow acceleration and no treadmill slope.

Effect of contrasted levels of habitual physical activity on metabolic flexibility.

The factors regulating the body's ability to switch from fat to carbohydrate oxidation in response to fuel availability changes, or metabolic flexibility (MF), are currently intensively investigated in the context of metabolic diseases. Although numerous metabolic diseases are associated with sedentary behaviors and metabolic inflexibility, the effect of habitual physical activity level (PAL) on MF regulation is surprisingly poorly known. We investigated how PAL affects MF in cross-sectional and interventional studies. MF was assessed in 44 subjects: normal-weight and overweight sedentary men submitted to 2 mo of exercise at current recommendations, normal-weight active men submitted to 1 mo of reduced PAL and normal-weight women submitted to 1 mo of bed rest, with or without exercise. MF was evaluated, before and after interventions, following two standard meals as the relationship between individual mathematical variances in insulin and nonprotein respiratory quotient (NPRQ) daily kinetics. Daily NPRQ and insulin variances differed according to habitual PAL (P = 0.002 and P = 0.009, respectively); active subjects had higher variances in NPRQ for lower variances in insulin than sedentary subjects, indicating a better MF. Detraining increased insulin variance (P = 0.009) and decreased NPRQ variance (P = 0.003), while training tended to have opposite effects. Insulin and NPRQ variances were negatively related along the PAL continuum (R(2) = 0.70, P < 0.001). Variance in NPRQ was also positively related to PAL (R(2) = 0.52, P < 0.001). By assessing MF with mathematical surrogates in conditions of daily pattern in meal's intake, we showed that habitual PAL is associated with MF status, and that MF is modulated by changes in PAL.

Activity energy expenditure is a major determinant of dietary fat oxidation and trafficking, but the deleterious effect of detraining is more marked than the beneficial effect of training at current recommendations.

BACKGROUND: Previous studies suggested that physical activity energy expenditure (AEE) is a major determinant of dietary fat oxidation, which is a central component of fat metabolism and body weight regulation. OBJECTIVE: We tested this hypothesis by investigating the effect of contrasted physical activity levels on dietary saturated and monounsaturated fatty acid oxidation in relation to insulin sensitivity while controlling energy balance. DESIGN: Sedentary lean men (n = 10) trained for 2 mo according to the current guidelines on physical activity, and active lean men (n = 9) detrained for 1 mo by reducing structured and spontaneous activity. Dietary [d31]palmitate and [1-¹³C]oleate oxidation and incorporation into triglyceride-rich lipoproteins and nonesterified fatty acid, AEE, and muscle markers were studied before and after interventions. RESULTS: Training increased palmitate and oleate oxidation by 27% and 20%, respectively, whereas detraining reduced them by 31% and 13%, respectively (P < 0.05 for all). Changes in AEE were positively correlated with changes in oleate (R² = 0.62, P < 0.001) and palmitate (R² = 0.66, P < 0.0001) oxidation. The d31-palmitate appearance in nonesterified fatty acid and very-low-density lipoprotein pools was negatively associated with changes in fatty acid translocase CD36 (R² = 0.30), fatty acid transport protein 1 (R² = 0.24), and AcylCoA synthetase long chain family member 1 (ACSL1) (R² = 0.25) expressions and with changes in fatty acid binding protein expression (R² = 0.33). The d31-palmitate oxidation correlated with changes in ACSL1 (R² = 0.39) and carnitine palmitoyltransferase 1 (R² = 0.30) expressions (P < 0.05 for all). Similar relations were observed with oleate. Insulin response was associated with AEE (R² = 0.34, P = 0.02) and oleate (R² = 0.52, P < 0.01) and palmitate (R² = 0.62, P < 001) oxidation. CONCLUSION: Training and detraining modified the oxidation of the 2 most common dietary fats, likely through a better trafficking and uptake by the muscle, which was negatively associated with whole-body insulin sensitivity.

Regulation of energy balance during long-term physical inactivity induced by bed rest with and without exercise training.

BACKGROUND: Short-term physical inactivity affects energy balance and is considered conducive to weigh gain. Long-term effects are unknown. OBJECTIVE: The objective of the study was to use a bed-rest model to determine the long-term effects of physical inactivity on energy balance regulation and test the effect of exercise training on energy balance adjustment to physical inactivity. DESIGN: Sixteen lean women were divided into two groups (n = 8 each): a control group subjected to a strict 60-d bed rest and an exercise group subjected to a combined aerobic/resistive exercise training concomitantly to bed rest. Body composition, spontaneous energy intake, hunger, total energy expenditure (TEE), and fasting gut hormones were measured. RESULTS: Based on bed-rest-induced body composition changes, the control group were in slight negative energy balance (-0.4 +/- 0.4 MJ/d; P = 0.01 vs. zero), essentially due to muscle atrophy (P < 0.001 vs. zero). The stable fat mass (P = 0.19 vs. zero), and the matching between spontaneous energy intake and TEE indicated, however, a stable energy balance. Hunger and gut hormones remained unchanged during the bed rest. In the exercise group, TEE was 24% higher than in the control group (P = 0.004). Unexpectedly, desire to consume food (P = 0.025) decreased and spontaneous energy intake (P = NS) was not stimulated, promoting a negative energy balance (-1.1 +/- 0.5 MJ/d, P = 0.0003 vs. zero). CONCLUSIONS: Energy balance is regulated during 2 months of physical inactivity, contrasting with short-term experiments. Conversely, exercise-induced energy expenditure in bed-resting subjects who have no spontaneous physical activity did not induce hunger and promoted a negative energy balance, suggesting a potential role of nonexercise physical activities in energy balance regulation.

The grey mouse lemur uses season-dependent fat or protein sparing strategies to face chronic food restriction.

During moderate calorie restriction (CR) the heterotherm Microcebus murinus is able to maintain a stable energy balance whatever the season, even if only wintering animals enter into torpor. To understand its energy saving strategies to respond to food shortages, we assessed protein and energy metabolisms associated with wintering torpor expression or summering torpor avoidance. We investigated body composition, whole body protein turnover, and daily energy expenditure (DEE), during a graded (40 and 80%) 35-day CR in short-days (winter; SD40 and SD80, respectively) and long-days (summer; LD40 and LD80, respectively) acclimated animals. LD40 animals showed no change in fat mass (FM) but a 12% fat free mass (FFM) reduction. Protein balance being positive after CR, the FFM loss was early and rapid. The 25% DEE reduction, in LD40 group was mainly explained by FFM changes. LD80 animals showed a steady body mass loss and were excluded from the CR trial at day 22, reaching a survival-threatened body mass. No data were available for this group. SD40 animals significantly decreased their FM level by 21%, but maintained FFM. Protein sparing was achieved through a 35 and 39% decrease in protein synthesis and catabolism (protein turnover), respectively, overall maintaining nitrogen balance. The 21% reduction in energy requirement was explained by the 30% nitrogen flux drop but also by torpor as DEE FFM-adjusted remained 13% lower compared to ad-libitum. SD80 animals were unable to maintain energy and nitrogen balances, losing both FM and FFM. Thus summering mouse lemurs equilibrate energy balance by a rapid loss of active metabolic mass without using torpor, whereas wintering animals spare protein and energy through increased torpor expression. Both strategies have direct fitness implication: 1) to maintain activities at a lower body size during the mating season and 2) to preserve an optimal wintering muscle mass and function.

Metabolic fate of saturated and monounsaturated dietary fats: the Mediterranean diet revisited from epidemiological evidence to cellular mechanisms.

Increasing evidence indicates favourable effects of the Mediterranean diet, partly associated to its monounsaturated fatty acids (MUFA) content on both obesity and diabetes. However, neither the underlying mechanisms by which the Mediterranean diet exerts its protective effect, nor the interplay with other environmental factors (i.e. physical activity), are fully characterised. In this review, we examined recent data on how the metabolic fate of MUFA and saturated fatty acids (SFA) differs. Because of differential packaging into lipoproteins, hydrolysis of triacylglycerol-rich lipoproteins by lipoprotein lipase and transport into oxidative tissues, MUFA are oxidised more than SFA. This high MUFA oxidation favour lipid oxidation and according to the oxidative balance concept reduces the risk of obesity. It also improves the intra-muscular triacylglycerol turnover, which mitigates the SFA-induced accumulation of diacylglycerol and ceramides, and thus protects the insulin sensitivity and cell viability. Finally, physical activity through its action on the energy turnover differentially regulates the metabolism of SFA and MUFA. The putative combined role of AMP-activated kinase and mitochondrial glycerol-3-phosphate transferase on the intra-muscular partitioning of MUFA and SFA provides new areas of research to better understand the beneficial effects of the Mediterranean diet and physical activity on obesity and diabetes.

Gut hormones in relation to body mass and torpor pattern changes during food restriction and re-feeding in the gray mouse lemur.

Potential implications of gut hormones in body mass and torpor and behavioral pattern changes induced by an incremental (40 and 80%) calorie restriction (CR) in long-days (LD, summer) and short-days (SD, winter) were investigated in gray mouse lemurs. Only 80% food-deprived LD and SD animals showed a continuous mass loss resulting in a 10 and 15% mass reduction, respectively. Ghrelin levels of all food-deprived groups increased by 2.6-fold on average and remained high after re-feeding while peptide YY (PYY) levels increased by 3.8-fold only in LD animals under 80% CR. In the re-fed SD group, body mass was positively associated with ghrelin and negatively associated with PYY, while no correlations were noted in the re-fed LD animals. Plasma glucagon-like peptide-1 (GLP-1) increased by 2.9-fold only in LD food-restricted mouse lemurs and was negatively associated with the minimal body temperature. No significant correlations were reported in food-deprived SD animals. These results suggest that ghrelin, PYY and GLP-1 may be related to pre-wintering fattening mechanisms and to the modulation of torpor expression, respectively. Such observation clearly warrants further investigations, but it opens an interesting area of research in torpor regulation.

Physical inactivity differentially alters dietary oleate and palmitate trafficking.

OBJECTIVE: Obesity and diabetes are characterized by the incapacity to use fat as fuel. We hypothesized that this reduced fat oxidation is secondary to a sedentary lifestyle. RESEARCH DESIGN AND METHODS: We investigated the effect of a 2-month bed rest on the dietary oleate and palmitate trafficking in lean women (control group, n = 8) and the effect of concomitant resistance/aerobic exercise training as a countermeasure (exercise group, n = 8). Trafficking of stable isotope-labeled dietary fats was combined with muscle gene expression and magnetic resonance imaging-derived muscle fat content analyses. RESULTS: In the control group, bed rest increased the cumulative [1-(13)C]oleate and [d(31)]palmitate appearance in triglycerides (37%, P = 0.009, and 34%, P = 0.016, respectively) and nonesterified fatty acids (NEFAs) (37%, P = 0.038, and 38%, P = 0.002) and decreased muscle lipoprotein lipase (P = 0.043) and fatty acid translocase CD36 (P = 0.043) mRNA expressions. Plasma NEFA-to-triglyceride ratios for [1-(13)C]oleate and [d(31)]palmitate remained unchanged, suggesting that the same proportion of tracers enters the peripheral tissues after bed rest. Bed rest did not affect [1-(13)C]oleate oxidation but decreased [d(31)]palmitate oxidation by -8.2 +/- 4.9% (P < 0.0001). Despite a decreased spontaneous energy intake and a reduction of 1.9 +/- 0.3 kg (P = 0.001) in fat mass, exercise training did not mitigate these alterations but partially maintained fat-free mass, insulin sensitivity, and total lipid oxidation in fasting and fed states. In both groups, muscle fat content increased by 2.7% after bed rest and negatively correlated with the reduction in [d(31)]palmitate oxidation (r(2) = 0.48, P = 0.003). CONCLUSIONS: While saturated and monounsaturated fats have similar plasma trafficking and clearance, physical inactivity affects the partitioning of saturated fats toward storage, likely leading to an accumulation of palmitate in muscle fat.

Protein-mediated fatty acid uptake: regulation by contraction, AMP-activated protein kinase, and endocrine signals.

Fatty acid transport into heart and skeletal muscle occurs largely through a highly regulated protein-mediated mechanism involving a number of fatty acid transporters. Chronically altered muscle activity (chronic muscle stimulation, denervation) alters fatty acid transport by altering the expression of fatty acid transporters and (or) their subcellular location. Chronic exposure to leptin downregulates while insulin upregulates fatty acid transport by altering concomitantly the expression of fatty acid transporters. Fatty acid transport can also be regulated within minutes, by muscle contraction, AMP-activated protein kinase activation, leptin, and insulin, through induction of the translocation of fatty acid translocase (FAT)/CD36 from its intracellular depot to the plasma membrane. In insulin-resistant muscle, a permanent relocation of FAT/CD36 to the sarcolemma appears to account for the excess accretion of intracellular lipids that interfere with insulin signaling. Recent work has also shown that FAT/ CD36, but not plasma membrane associated fatty acid binding protein, is involved, along with carnitine palmitoyltransferase, in regulating mitochondrial fatty acid oxidation. Finally, studies in FAT/CD36 null mice indicate that this transporter has a key role in regulating fatty acid metabolism in muscle.