A mutation in the dynein heavy chain gene compensates for energy deficit of mutant SOD1 mice and increases potentially neuroprotective IGF-1

International audienceBACKGROUND: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by a progressive loss of motor neurons. ALS patients, as well as animal models such as mice overexpressing mutant SOD1s, are characterized by increased energy expenditure. In mice, this hypermetabolism leads to energy deficit and precipitates motor neuron degeneration. Recent studies have shown that mutations in the gene encoding the dynein heavy chain protein are able to extend lifespan of mutant SOD1 mice. It remains unknown whether the protection offered by these dynein mutations relies on a compensation of energy metabolism defects. RESULTS: SOD1(G93A) mice were crossbred with mice harboring the dynein mutant Cramping allele (Cra/+ mice). Dynein mutation increased adipose stores in compound transgenic mice through increasing carbohydrate oxidation and sparing lipids. Metabolic changes that occurred in double transgenic mice were accompanied by the normalization of the expression of key mRNAs in the white adipose tissue and liver. Furthermore, Dynein Cra mutation rescued decreased post-prandial plasma triglycerides and decreased non esterified fatty acids upon fasting. In SOD1(G93A) mice, the dynein Cra mutation led to increased expression of IGF-1 in the liver, increased systemic IGF-1 and, most importantly, to increased spinal IGF-1 levels that are potentially neuroprotective. CONCLUSIONS: These findings suggest that the protection against SOD1(G93A) offered by the Cramping mutation in the dynein gene is, at least partially, mediated by a reversal in energy deficit and increased IGF-1 availability to motor neurons

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

CORPS GRAS ET OBESITE Acides gras alimentaires et obésité : aspects qualitatifs et quantitatifs

Les triacylglycérols (TAG) adipocytaires représentent la principale forme de stockage des acides gras. Les TAG contiennent un mélange complexe d’acides gras qui diffèrent très nettement par leur structure moléculaire. En effet, les TAG adipocytaires contiennent un vaste spectre d’acides gras, allant en longueur de chaîne de 12 à 24 atomes de carbone et en insaturation de 0 à 6 doubles liaisons [1]. La nature des acides gras stockés dans le tissu adipeux dépend principalement de la composition en acides gras de l’alimentation [2, 3]. Le contrôle des acides gras et notamment des acides gras polyinsaturés (AGPI) stockés dans le tissu adipeux est encore assez peu compris. Si la composition en acides gras des TAG adipocytaires reflète largement celle de l’alimentation, elle ne la suit pas précisément [3]. Ainsi, la proportion en AGPI dans le tissu adipeux est systématiquement plus faible que celle du régime [2]. Une incorporation et une mobilisation sélectives de certains acides gras pourraient en partie expliquer ces observations. En effet, les AGPI sont globalement faiblement incorporés et assez facilement mobilisés. Nous n’aborderons pas ici la sélectivité du métabolisme adipocytaire des acides gras que nous avons précédemment rapportée à nos lecteurs (ocl, 5 : 199-205). Dans le cadre de cette revue, nous centrerons notre propos sur les relations entres acides gras alimentaires, développement du tissu adipeux et régulation de l’expression de gènes hépatiques et adipocytaires

CORPS GRAS ET OBESITE Acides gras alimentaires et obésité : aspects qualitatifs et quantitatifs

Les triacylglycérols (TAG) adipocytaires représentent la principale forme de stockage des acides gras. Les TAG contiennent un mélange complexe d’acides gras qui diffèrent très nettement par leur structure moléculaire. En effet, les TAG adipocytaires contiennent un vaste spectre d’acides gras, allant en longueur de chaîne de 12 à 24 atomes de carbone et en insaturation de 0 à 6 doubles liaisons [1]. La nature des acides gras stockés dans le tissu adipeux dépend principalement de la composition en acides gras de l’alimentation [2, 3]. Le contrôle des acides gras et notamment des acides gras polyinsaturés (AGPI) stockés dans le tissu adipeux est encore assez peu compris. Si la composition en acides gras des TAG adipocytaires reflète largement celle de l’alimentation, elle ne la suit pas précisément [3]. Ainsi, la proportion en AGPI dans le tissu adipeux est systématiquement plus faible que celle du régime [2]. Une incorporation et une mobilisation sélectives de certains acides gras pourraient en partie expliquer ces observations. En effet, les AGPI sont globalement faiblement incorporés et assez facilement mobilisés. Nous n’aborderons pas ici la sélectivité du métabolisme adipocytaire des acides gras que nous avons précédemment rapportée à nos lecteurs (ocl, 5 : 199-205). Dans le cadre de cette revue, nous centrerons notre propos sur les relations entres acides gras alimentaires, développement du tissu adipeux et régulation de l’expression de gènes hépatiques et adipocytaires

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

Hormonal changes and energy substrate availability during the hibernation cycle of Syrian hamsters

International audienceAnimals have to adapt to seasonal variations in food resources and temperature. Hibernation is one of the most efficient means used by animals to cope with harsh winter conditions, where survival is achieved through a significant decrease in energy expenditure. The hibernation period is constituted by a succession of torpor bouts (hypometabolism and decrease in body temperature) and periodic arousals (eumetabolism and euthermia). Some species feed during these periodic arousals, and thus show different metabolic adaptations to fat-storing species that fast throughout the hibernation period. Our study aims to define these metabolic adaptations, including hormone (insulin, glucagon, leptin, adiponectin, GLP-1, GiP) and metabolite (glucose, free fatty acids, triglycerides, urea) profiles together with body composition adjustments. Syrian hamsters were exposed to varied photoperiod and temperature conditions mimicking different phases of the hibernation cycle: a long photoperiod at 20°C (LP20 group), a short photoperiod at 20°C (SP20 group), and a short photoperiod at 8°C (SP8). SP8 animals were sampled either at the beginning of a torpor bout (Torpor group) or at the beginning of a periodic arousal (Arousal group). We show that fat store mobilization in hamsters during torpor bouts is associated with decreased circulating levels of glucagon, insulin, leptin, and an increase in adiponectin. Refeeding during periodic arousals results in a decreased free fatty acid plasma concentration and an increase in glycaemia and plasma incretin concentrations. Reduced incretin and increased adiponectin levels are therefore in accordance with the changes in nutrient availability and feeding behavior observed during the hibernation cycle of Syrian hamsters