Elisa Le Roux

After a meal, it is generally assumed that tissue non-esterified fatty acids (NEFA) uptake falls in proportion of the reduction of systemic NEFA appearance from insulin-mediated suppression of adipose tissue lipolysis. Here, we combined dynamic [ ¹¹ C]palmitate PET/CT, stable isotope tracers, and MRI to measure palmitate uptake, oxidation, and esterification in the heart, liver, skeletal muscle, and subcutaneous and visceral adipose tissue, in the fasted state and 60min after a mixed meal in individuals with prediabetes. Net palmitate uptake decreased in all tissues, but most tissues extracted a larger fraction of circulating palmitate after the meal. The intracellular fate of palmitate differed between organs. The heart shifted toward oxidation, the liver toward esterification, maintaining VLDL-palmitate release, and this shift was smaller in individuals with more liver fat. Both adipose depots increased fractional esterification, and visceral fat almost stopped releasing palmitate. Thus, plasma NEFA overestimates the postprandial reduction in lean tissue NEFA exposure. Highlights: After a meal, net palmitate uptake fall in all tissues but extraction rises in most After a meal, the liver directs palmitate toward esterification and the heart toward oxidation Plasma NEFA level underestimate lean tissue NEFA exposure after a meal in prediabetes

Les études de simulation de microgravité ont mis en évidence des adaptations du métabolisme intermédiaire et une diminution de la flexibilité métabolique (c-à-d la capacité à ajuster l’utilisation des substrats en fonction des changements de leur disponibilité), pouvant entrainer des conséquences néfastes sur la performance et la santé des astronautes. Dans le contexte de la nouvelle phase exploratoire spatiale, ce travail de thèse a cherché à combler les lacunes actuelles pour mieux comprendre l’impact de la microgravité sur la flexibilité métabolique et les mécanismes cellulaires et moléculaires sous-jacents. Nous avons montré chez des hommes sains que seuls 5 jours d’exposition à la microgravité par immersion sèche induisent une diminution de la sensibilité à l’insuline, une hypertriglycéridémie et une accumulation de lipides hépatiques. Au niveau du muscle squelettique, une altération de la voie de signalisation de l’insuline ainsi qu’une réduction de la flexibilité métabolique au glucose ont été notées. Cette dernière semble précéder l’altération de la flexibilité métabolique au niveau du corps entier. Chez des astronautes ayant séjourné au moins 3 mois à bord de la station spatiale internationale, la flexibilité métabolique et l’oxydation postprandiale des substrats n’ont pas été affectées en moyenne. Toutefois les variabilités inter-individuelles ont mis en évidence des relations entre la flexibilité métabolique, l’exercice, le régime alimentaire et les changements de composition corporelle. Ces résultats apportent de nouveaux éléments pour aider à la préparation des futures missions de longue durée. Enfin, ces travaux ont des retombées sur terre en aidant à mieux comprendre les effets de l’inactivité physique sur le développement de pathologies métaboliques.

Five days of dry immersion led to reduced cardiovascular fitness, muscle atrophy, hepatic fat accumulation, and lower glucose tolerance. These alterations occur despite no detectable changes in whole body fat and carbohydrate oxidation following a carbohydrate-rich meal. In cultured primary myotubes, insulin action and metabolic flexibility (fuel switching) are impaired. Early alterations in intrinsic muscle cell metabolism likely reflect rapid epigenetic imprinting of satellite cells and may contribute to systemic metabolic disturbances induced by physical inactivity.

Bedrest shifts fasting and postprandial fuel selection towards carbohydrate use over lipids, potentially affecting astronauts’ performance and health. We investigated whether this change occurs in astronauts after at least 3 months onboard the International Space Station (ISS). We further explored the associations with diet, physical activity (PA), and body composition. Before and during spaceflight, respiratory quotient (RQ), carbohydrate, and fat oxidation were measured by indirect calorimetry before and following a standardized meal in 11 males (age = 45.7 [SD 7.7] years, BMI = 24.3 [2.1] kg m⁻²). Postprandial substrate use was determined by 0-to-260 min postprandial incremental area under the curve (iAUC) of nutrient oxidation and the difference between maximal postprandial and fasting RQ (ΔRQ). Food quotient (FQ) was calculated from diet logs. Fat (FM) and fat-free mass (FFM) were measured by hydrometry and PA by accelerometry and diary logs. Spaceflight increased fasting RQ (P = 0.01) and carbohydrate oxidation (P = 0.04) and decreased fasting lipid oxidation (P < 0.01). An increase in FQ (P < 0.001) indicated dietary modifications onboard the ISS. Spaceflight-induced RQ changes adjusted for ground RQ correlated with inflight FQ (P < 0.01). In postprandial conditions, nutrient oxidation and ΔRQ were unaffected on average. Lipid oxidation changes negatively correlated with FFM changes and inflight aerobic exercise and positively with FM changes. The opposite was observed for carbohydrate oxidation. ΔRQ changes were negatively and positively related to FM and FFM changes, respectively. In conclusion, fasting substrate oxidation shift observed during spaceflight may primarily result from dietary modifications. Between-astronaut variability in postprandial substrate oxidation depends on body composition changes and inflight PA.

Simulated microgravity is known to induce a shift in fasting fuel selection in favor of carbohydrate use and in detriment of lipids, and to reduce metabolic flexibility (MF), i.e., the capacity to adjust fuel oxidation to changes in substrate availability and energy demand. Given their potential adverse effects on performance and health, we aimed to determine whether such metabolic alterations occur in astronauts during long-term spaceflights. We further explored the associations with diet, physical activity, and body composition. Before and after at least three months onboard the International Space Station, respiratory quotient (RQ), carbohydrate and fat oxidation were measured by indirect calorimetry before and following a standardized meal in 11 male astronauts (age=45.7 [SD 7.7] years, BMI=24.3 [2.1] kg/m²). MF was determined by 0-to-260 min postprandial incremental area under the curve (iAUC) of nutrient oxidation and the difference between maximal postprandial and fasting RQ (ΔRQ). The food quotient (FQ) was calculated from diet logs. Fat (FM) and fat-free mass (FFM) were measured by hydrometry and physical activity by accelerometry and diary logs. Three months in space increased fasting RQ (P=0.01) and carbohydrate oxidation (P=0.04), and decreased fasting lipid oxidation (P<0.01). An increase in FQ (P<0.001) indicated a shift in diet composition. Spaceflight-induced changes in RQ adjusted on ground RQ were associated with inflight FQ (P<0.01). No changes were noted in mean postprandial nutrient oxidation or ΔRQ. Individual postprandial lipid oxidation iAUC was negatively associated with changes in FFM and inflight aerobic exercise, and positively with changes in FM. The opposite was observed with postprandial carbohydrate oxidation. Changes in ΔRQ were negatively and positively related to FM and FFM changes, respectively. In conclusion, the shift in fasting substrate oxidation observed during spaceflight is essentially driven by dietary modifications. Between-astronaut variability in postprandial substrate oxidation depends on body composition changes and inflight physical activity.

Objective Body mass (BM) loss and body composition (BC) changes threaten astronauts’ health and mission success. However, the energetic contribution of the exercise countermeasure to these changes has never been investigated during long-term missions. We studied energy balance and BC in astronauts during 6-month missions onboard the International Space Station. Methods Before and after at least 3 months in space, BM, BC, total and activity energy expenditure (TEE and AEE) were measured using the doubly labeled water method in 11 astronauts (2011–2017). Physical activity (PA) was assessed by the SensewearPro® activity-device. Results Three-month spaceflight decreased BM (− 1.20 kg [SE 0.5]; P = 0.04), mainly due to non-significant fat-free mass loss (FFM; − 0.94 kg [0.59]). The decrease in walking time (− 63.2 min/day [11.5]; P < 0.001) from preflight was compensated by increases in non-ambulatory activities (+ 64.8 min/day [18.8]; P < 0.01). Average TEE was unaffected but a large interindividual variability was noted. Astronauts were stratified into those who maintained (stable_TEE; n = 6) and those who decreased (decreased_TEE; n = 5) TEE and AEE compared to preflight data. Although both groups lost similar BM, FFM was maintained and FM reduced in stable_TEE astronauts, while FFM decreased and FM increased in decreased_TEE astronauts (estimated between-group-difference (EGD) in ΔFFMindex [FFMI] 0.87 kg/m², 95% CI + 0.32 to + 1.41; P = 0.01, ΔFMindex [FMI] − 1.09 kg/m², 95% CI − 2.06 to − 0.11 kg/m²; P = 0.03). The stable_TEE group had higher baseline FFMI, and greater baseline and inflight vigorous PA than the decreased_TEE group (P < 0.05 for all). ΔFMI and ΔFFMI were respectively negatively and positively associated with both ΔTEE and ΔAEE. Conclusion Both ground fitness and inflight overall PA are associated with spaceflight-induced TEE and BC changes and thus energy requirements. New instruments are needed to measure real-time individual changes in inflight energy balance components.

Physical inactivity, i.e. not reaching the recommended level of physical activity (PA), and sedentary behaviours (SB), i.e. sitting time, have been associated with increased risk for common metabolic diseases. Recent epidemiological data suggest that high volumes of SB are detrimental to metabolic health, even in the presence of regular exercise, i.e. moderate/vigorous PA. This suggests that the health effects of SB are independent from those of exercise. However, experimentally testing this hypothesis is complicated because of the difficulty in disassociating SB from PA. Bedrest studies, a traditional space science model, can offer new insights. In some bedrest studies, an exercise training protocol has been used to counteract the harmful effects of inactivity. While bedrest induces an inactive and sedentary state, exercise with bedrest represents a unique model of sedentary yet physically active people. Here, we review bedrest studies with and without exercise training. Although exercise training prevents the loss of muscle mass and function, even large volumes of exercise are not sufficient to fully counteract the negative metabolic adaptations triggered by inactivity. This observation supports the existence of independent adverse health effects of SB, but also the potential benefits of non‐exercise activity, i.e. daily living light PA. We gathered available data to examine the complex relationships between exercise, non‐exercise activity, SB and health outcomes. Given the large amount of SB in modern societies, the sole promotion of exercise, i.e. moderate/vigorous PA may be insufficient, and promotion of light PA may be a complimentary approach to improve health. image