The Torpid State:Recent Advances in Metabolic Adaptations and Protective Mechanisms(dagger)

Torpor and hibernation are powerful strategies enabling animals to survive periods of low resource availability. The state of torpor results from an active and drastic reduction of an individual's metabolic rate (MR) associated with a relatively pronounced decrease in body temperature. To date, several forms of torpor have been described in all three mammalian subclasses, i.e., monotremes, marsupials, and placentals, as well as in a few avian orders. This review highlights some of the characteristics, from the whole organism down to cellular and molecular aspects, associated with the torpor phenotype. The first part of this review focuses on the specific metabolic adaptations of torpor, as it is used by many species from temperate zones. This notably includes the endocrine changes involved in fat- and food-storing hibernating species, explaining biomedical implications of MR depression. We further compare adaptive mechanisms occurring in opportunistic vs. seasonal heterotherms, such as tropical and sub-tropical species. Such comparisons bring new insights into the metabolic origins of hibernation among tropical species, including resistance mechanisms to oxidative stress. The second section of this review emphasizes the mechanisms enabling heterotherms to protect their key organs against potential threats, such as reactive oxygen species, associated with the torpid state. We notably address the mechanisms of cellular rehabilitation and protection during torpor and hibernation, with an emphasis on the brain, a central organ requiring protection during torpor and recovery. Also, a special focus is given to the role of an ubiquitous and readily-diffusing molecule, hydrogen sulfide (H2S), in protecting against ischemia-reperfusion damage in various organs over the torpor-arousal cycle and during the torpid state. We conclude that (i) the flexibility of torpor use as an adaptive strategy enables different heterothermic species to substantially suppress their energy needs during periods of severely reduced food availability, (ii) the torpor phenotype implies marked metabolic adaptations from the whole organism down to cellular and molecular levels, and (iii) the torpid state is associated with highly efficient rehabilitation and protective mechanisms ensuring the continuity of proper bodily functions. Comparison of mechanisms in monotremes and marsupials is warranted for understanding the origin and evolution of mammalian torpor

Intestinal gluconeogenesis and glucose transport according to body fuel availability in rats

Intestinal hexose absorption and gluconeogenesis have been studied in relation to refeeding after two different fasting phases: a long period of protein sparing during which energy expenditure is derived from lipid oxidation (phase II), and a later phase characterized by a rise in plasma corticosterone triggering protein catabolism (phase III). Such a switch in body fuel uses, leading to changes in body reserves and gluconeogenic precursors, could modulate intestinal gluconeogenesis and glucose transport. The gene and protein levels, and the cellular localization of the sodium-glucose cotransporter SGLT1, and of GLUT5 and GLUT2, as well as that of the key gluconeogenic enzymes phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatase (Glc6Pase) were measured. PEPCK and Glc6Pase activities were also determined. In phase III fasted rats, SGLT1 was up-regulated and intestinal glucose uptake rates were higher than in phase II fasted and fed rats. PEPCK and Glc6Pase mRNA, protein levels and activities also increased in phase III. GLUT5 and GLUT2 were down-regulated throughout the fast, but increased after refeeding, with GLUT2 recruited to the apical membrane. The increase in SGLT1 expression during phase III may allow glucose absorption at low concentrations as soon as food is available. Furthermore, an increased epithelial permeability due to fasting may induce a paracellular movement of glucose. In the absence of intestinal GLUT2 during fasting, Glc6Pase could be involved in glucose release to the bloodstream via membrane trafficking. Finally, refeeding triggered GLUT2 and GLUT5 synthesis and apical recruitment of GLUT2, to absorb larger amounts of hexoses

Intestinal morphology,cellular dynamics and physiology according to body fuel availability in rats

L'épithélium de l'intestin grêle est atrophié après un jeûne court défini comme phase de mobilisation des réserves lipidiques (phase II), et surtout après un jeûne prolongé caractérisé par un catabolisme protéique élevé (phase III). Au niveau cellulaire cependant, alors que la phase II du jeûne est marquée par une diminution de la prolifération et de la migration cellulaires, la phase III présente une augmentation de ces mécanismes. La phase III se caractérise aussi par un arrêt de l'apoptose intestinale qui permettrait de préserver les entérocytes et donc l'absorption de nutriments dès réalimentation. La reprise de l'activité cellulaire et l'arrêt de l'apoptose en phase III seraient induits par une baisse des cytokines TNF et TGF 1 et du facteur de transcription intestinal Cdx2. L'augmentation de la prolifération cellulaire initiée déjà pendant la phase III du jeûne entraînerait une restauration de l'épithélium intestinal après réalimentation toute aussi rapide qu après un jeûne plus court.L'expression des transporteurs actifs PepT1 et SGLT1 ainsi que l'activité néoglucogénique intestinale sont stimulées au cours de la phase III mais pas pendant la phase II du jeûne. L'augmentation de la protéine SGLT1 pendant la phase III du jeûne permet une absorption immédiate de glucose dès réalimentation. La présence en grande quantité de la protéine PepT1 en phase III du jeûne devrait permettre une absorption de peptides et donc un apport azoté dès réalimentation. La réalimentation enfin, stimule l'expression des transporteurs facilités GLUT5, GLUT2 et FATP4. Lorsque le jeûne se prolonge et que l'animal atteint un seuil critique de déplétion de ses réserves énergétiques, l'activation de mécanismes cellulaires et moléculaires spécifiques entraînerait une optimisation de la capacité d'absorption des nutriments par la muqueuse de l'intestin grêle dès réalimentation.After the early adaptation to fasting (phase I), an atrophy of the intestinal mucosa occurs during the period which is characterized by the mobilization of fat stores and an efficient protein sparing. This atrophy is aggravated during the further rise in protein utilization (phase III). Cell proliferation and migration decrease during phase II, but strongly increase during a phase III fast and may therefore initiate mucosal repair well before food becomes available. Also, a phase III fast induces an arrest in intestinal epithelial apoptosis at the tip of the villi, suggesting preservation of absorptive cells. The lack of apoptosis and initiation of cell proliferation during phase III fasting may be triggered by a decrease in the cytokines TGFb1, and TNF and in the intestine specific transcription factor Cdx2. They are concomitant with a peak of locomotor activity in these animals induced by a rise in plasma corticosterone and reflecting the search for food. Intestinal gluconeogenesis is increased during a phase III fast, when the availability of amino acids used as precursors raises. At the same time, the active glucose and peptide transporters are enhanced. Glucose can then, be immediately absorbed at low concentrations through SGLT1. Glucose and peptides should be used as a source of energy and peptides should also provide body protein precursors. Finally, refeeding following either a phase II or a phase III fast stimulates facilitative fatty acids and glucose transports, so that large amounts of these metabolites can be transported from the intestinal lumen to the blood stream and provides energy. The unaltered and even increased absorption capabilities of the intestine during a phase III fast when the animal reaches a low threshold in nutrient reserves, coincides with a search for food activity and could permit food assimilation immediately after refeeding

Mécanismes cellulaires et moléculaires de l'absorption intestinale au cours du jeûne et après réalimentation.

L'épithélium de l’intestin grêle est atrophié après un jeûne court défini comme phase de mobilisation des réserves lipidiques (phase II), et surtout après un jeûne prolongé caractérisé par un catabolisme protéique élevé (phase III). Au niveau cellulaire cependant, alors que la phase II du jeûne est marquée par une diminution de la prolifération et de la migration cellulaires, la phase III présente une augmentation de ces mécanismes. La phase III se caractérise aussi par un arrêt de l’apoptose intestinale qui permettrait de préserver les entérocytes et donc l’absorption de nutriments dès réalimentation. La reprise de l’activité cellulaire et l’arrêt de l’apoptose en phase III seraient induits par une baisse des cytokines TNFalpha et TGFbeta1 et du facteur de transcription intestinal Cdx2. L’augmentation de la prolifération cellulaire initiée déjà pendant la phase III du jeûne entraînerait une restauration de l’épithélium intestinal après réalimentation toute aussi rapide qu’après un jeûne plus court. L’expression des transporteurs actifs PepT1 et SGLT1 ainsi que l’activité néoglucogénique intestinale sont stimulées au cours de la phase III mais pas pendant la phase II du jeûne. L’augmentation de la protéine SGLT1 pendant la phase III du jeûne permet une absorption immédiate de glucose dès réalimentation. La présence en grande quantité de la protéine PepT1 en phase III du jeûne devrait permettre une absorption de peptides et donc un apport azoté dès réalimentation. La réalimentation enfin, stimule l’expression des transporteurs facilités GLUT5, GLUT2 et FATP4. Lorsque le jeûne se prolonge et que l’animal atteint un seuil critique de déplétion de ses réserves énergétiques, l’activation de mécanismes cellulaires et moléculaires spécifiques entraînerait une optimisation de la capacité d’absorption des nutriments par la muqueuse de l’intestin grêle dès réalimentation. After the early adaptation to fasting (phase I), an atrophy of the intestinal mucosa occurs during the period which is characterized by the mobilization of fat stores and an efficient protein sparing. This atrophy is aggravated during the further rise in protein utilization (phase III). Cell proliferation and migration decrease during phase II, but strongly increase during a phase III fast and may therefore initiate mucosal repair well before food becomes available. Also, a phase III fast induces an arrest in intestinal epithelial apoptosis at the tip of the villi, suggesting preservation of absorptive cells. The lack of apoptosis and initiation of cell proliferation during phase III fasting may be triggered by a decrease in the cytokines TGFbeta1, and TNFalpha and in the intestine specific transcription factor Cdx2. They are concomitant with a peak of locomotor activity in these animals induced by a rise in plasma corticosterone and reflecting the search for food. Intestinal gluconeogenesis is increased during a phase III fast, when the availability of amino acids used as precursors raises. At the same time, the active glucose and peptide transporters are enhanced. Glucose can then, be immediately absorbed at low concentrations through SGLT1. Glucose and peptides should be used as a source of energy and peptides should also provide body protein precursors. Finally, refeeding following either a phase II or a phase III fast stimulates facilitative fatty acids and glucose transports, so that large amounts of these metabolites can be transported from the intestinal lumen to the blood stream and provides energy. The unaltered and even increased absorption capabilities of the intestine during a phase III fast when the animal reaches a low threshold in nutrient reserves, coincides with a search for food activity and could permit food assimilation immediately after refeeding

Intestinal morphology,cellular dynamics and physiology according to body fuel availability in rats

L'épithélium de l'intestin grêle est atrophié après un jeûne court défini comme phase de mobilisation des réserves lipidiques (phase II), et surtout après un jeûne prolongé caractérisé par un catabolisme protéique élevé (phase III). Au niveau cellulaire cAfter the early adaptation to fasting (phase I), an atrophy of the intestinal mucosa occurs during the period which is characterized by the mobilization of fat stores and an efficient protein sparing. This atrophy is aggravated during the further rise i

Adaptations métaboliques et digestives des espèces hibernantes

International audienceSome animals hibernate to spare energy during winter. They alternate torpor bouts (hypometabolism and hypothermia) and arousals (eumetabolism and euthermia). Food-storing species feed during these periodic arousals whereas fat-storing species fast throughout hibernation. This article describes the metabolic differences between these two strategies. In fat-storing animals, energy needs are covered by the hydrolysis of triglycerides of the white adipose tissue, whereas gluconeogenesis helps maintaining glycemia. In food-storing species, adiponectin stimulates lipolysis, which contributes to ketogenesis, but inhibits gluconeogenesis as a significant decrease in glycemia is observed during torpor. The maintenance of a functional digestive system ensures the absorption of nutrients and especially glucose during arousals in these species, allowing a transient restoration of glycemia. The quality of fat or food reserves determines the efficiency of hibernation and therefore, the body condition of animals at emergence, on which greatly depend survival and reproductive performances

Mécanismes cellulaires et moléculaires de l'absorption intestinale au cours du jeûne et après réalimentationTitre

L'épithélium de l intestin grêle est atrophié après un jeûne court défini comme phase de mobilisation des réserves lipidiques (phase II), et surtout après un jeûne prolongé caractérisé par un catabolisme protéique élevé (phase III). Au niveau cellulaire cependant, alors que la phase II du jeûne est marquée par une diminution de la prolifération et de la migration cellulaires, la phase III présente une augmentation de ces mécanismes. La phase III se caractérise aussi par un arrêt de l apoptose intestinale qui permettrait de préserver les entérocytes et donc l absorption de nutriments dès réalimentation. La reprise de l activité cellulaire et l arrêt de l apoptose en phase III seraient induits par une baisse des cytokines TNF et TGF 1 et du facteur de transcription intestinal Cdx2. L augmentation de la prolifération cellulaire initiée déjà pendant la phase III du jeûne entraînerait une restauration de l épithélium intestinal après réalimentation toute aussi rapide qu après un jeûne plus court.L expression des transporteurs actifs PepT1 et SGLT1 ainsi que l activité néoglucogénique intestinale sont stimulées au cours de la phase III mais pas pendant la phase II du jeûne. L augmentation de la protéine SGLT1 pendant la phase III du jeûne permet une absorption immédiate de glucose dès réalimentation. La présence en grande quantité de la protéine PepT1 en phase III du jeûne devrait permettre une absorption de peptides et donc un apport azoté dès réalimentation. La réalimentation enfin, stimule l expression des transporteurs facilités GLUT5, GLUT2 et FATP4. Lorsque le jeûne se prolonge et que l animal atteint un seuil critique de déplétion de ses réserves énergétiques, l activation de mécanismes cellulaires et moléculaires spécifiques entraînerait une optimisation de la capacité d absorption des nutriments par la muqueuse de l intestin grêle dès réalimentation.After the early adaptation to fasting (phase I), an atrophy of the intestinal mucosa occurs during the period which is characterized by the mobilization of fat stores and an efficient protein sparing. This atrophy is aggravated during the further rise in protein utilization (phase III). Cell proliferation and migration decrease during phase II, but strongly increase during a phase III fast and may therefore initiate mucosal repair well before food becomes available. Also, a phase III fast induces an arrest in intestinal epithelial apoptosis at the tip of the villi, suggesting preservation of absorptive cells. The lack of apoptosis and initiation of cell proliferation during phase III fasting may be triggered by a decrease in the cytokines TGFb1, and TNF and in the intestine specific transcription factor Cdx2. They are concomitant with a peak of locomotor activity in these animals induced by a rise in plasma corticosterone and reflecting the search for food. Intestinal gluconeogenesis is increased during a phase III fast, when the availability of amino acids used as precursors raises. At the same time, the active glucose and peptide transporters are enhanced. Glucose can then, be immediately absorbed at low concentrations through SGLT1. Glucose and peptides should be used as a source of energy and peptides should also provide body protein precursors. Finally, refeeding following either a phase II or a phase III fast stimulates facilitative fatty acids and glucose transports, so that large amounts of these metabolites can be transported from the intestinal lumen to the blood stream and provides energy. The unaltered and even increased absorption capabilities of the intestine during a phase III fast when the animal reaches a low threshold in nutrient reserves, coincides with a search for food activity and could permit food assimilation immediately after refeeding.STRASBOURG-Sc. et Techniques (674822102) / SudocSudocFranceF

Maintenance of a fully functional digestive system during hibernation in the European hamster, a food-storing hibernator

International audienceSome small mammals limit energy expenditure during winter conditions through torpor bouts, which are characterizedby a decrease in body temperature and metabolic rate. Individuals arise periodically from torpor to restorecritical functions requiring euthermia. Althoughmost of the species involved do not feed during hibernationand rely on body reserves to fulfil energy requirements (fat-storing species), others hoard food in a burrow(food-storing species) and can feed during interbout euthermy. Whereas fat-storing species undergo a markedatrophy of the digestive tract, food-storing species have to maintain a functional digestive system during hibernation.Our study aimed to evaluate the absorption capacities of a food-storing species, the European hamster,throughout the annual cycle. In vivo intestinal perfusions were conducted in different groups of hamsters(n = 5) during the different life periods, namely before hibernation, in torpor, during interbout euthermy, andduring summer rest. The triglyceride, non-esterified free fatty acid, starch, glucose and protein composition ofthe perfusate was evaluated before and after the 1 h perfusion of a closed intestinal loop. Triglyceride, starchand protein hydrolysis rates were similar in hibernating (torpid and euthermic) and non-hibernating hamsters.Intestinal absorption of free fatty acid was also similar in all groups. However, glucose uptake rate was higherduring hibernation than during the summer. In contrastwith fat-storing species, the intestinal absorption capacitiesof food-storing species are fully maintained during hibernation to optimize nutrient assimilation duringshort interbout euthermy. In particular, glucose uptake rate is increased during hibernation to restore glycaemiaand ensure glucose-dependent pathways

Microcomputed tomography: an accurate and low-cost method to assess body composition in small mammals

International audienceComputed tomography (CT) is widely used in humans for the assessment of regional body composition. It was particularly helpful in establishing the metabolic complications associated with high visceral fat volume. Physicists have only recently developed microCT systems dedicated to small animal imaging, with adequate resolution and dose delivery, but precision, accuracy and reproducibility remain to be determined