1,721,310 research outputs found
Liver mitochondrial properties from the obesity-resistant Lou/C rat.
No full textInternational audienceOBJECTIVE: The first objective was to evaluate the influence of caloric intake on liver mitochondrial properties. The second objective was aimed at determining the impact of increasing fat intake on these properties. DESIGN: Lou/C rats, displaying an inborn low caloric intake and resistant to diet-induced obesity, were compared to Wistar rats fed either ad libitum or pair-fed. An additional group of Lou/C rats were allowed to increase their fat intake by adjusting their diet from a standard high carbohydrate low-fat diet to a high-fat carbohydrate-free diet. MEASUREMENTS: Hydrogen peroxide (H(2)O(2)) generation, oxygen consumption rate (J(O(2))), membrane potential (DeltaPsi), activity of respiratory chain complexes, cytochrome contents, oxidative phosphorylation efficiency (OPE) and uncoupling protein 2 (UCP2) expression were determined in liver mitochondria. RESULTS: H(2)O(2) production was higher in Lou/C than Wistar rats with glutamate/malate and/or succinate, octanoyl-carnitine, as substrates. These mitochondrial features cannot be mimicked by pair-feeding Wistar rats and remained unaltered by increasing fat intake. Enhanced H(2)O(2) production by mitochondria from Lou/C rats is due to an increased reverse electron flow through the respiratory-chain complex I and a higher medium-chain acyl-CoA dehydrogenase activity. While J(O(2)) was similar over a large range of DeltaPsi in both strains, Lou/C rats were able to sustain higher membrane potential and respiratory rate. In addition, mitochondria from Lou/C rats displayed a decrease in OPE that cannot be explained by increased expression of UCP2 but rather to a slip in proton pumping by cytochrome oxidase. CONCLUSIONS: Liver mitochondria from Lou/C rats display higher reactive oxygen species (ROS) generation but to deplete upstream electron-rich intermediates responsible for ROS generation, these animals increased intrinsic uncoupling of cytochrome oxidase. It is likely that liver mitochondrial properties allowed this strain of rat to display higher insulin sensitivity and resist diet-induced obesity
Metabolic and hormonal responses to exercise in the anti-obese Lou/C rats
No full textOBJECTIVE: Lou/C rats are a substrain of Wistar rats that exhibit a spontaneous low caloric intake and no development of obesity with age. Recently, we reported that Lou/C rats, compared to equally food-restricted Wistar counterparts, show lower resting levels of plasma glucose, epinephrine and liver glycogen. To further explore this metabolic particularity, we used exercise (swimming 60 min) as a situation of high-energy demand, to test the ability of Lou/C rats to maintain euglycemia. DESIGN: Male Lou/C rats (14-week-old) were compared to age-matched male Wistar rats fed either ad libitum (WAL) or Wistar rats whose food was chronically restricted (WFR) to the same caloric intake as the Lou/C rats. RESULTS: In spite of low liver glycogen stores (~50% of normal values), Lou/C rats were able to maintain euglycemia during exercise even though liver glycogen breakdown was blunted. The decreased use of glycogen during exercise in Lou/C rats was associated with a reduced epinephrine response compared to WFR animals. By contrast, WFR were also able to maintain euglycemia during exercise but at the expense of a significant (P<0.01) decrease in liver and muscle glycogen content. Plasma free fatty acid and glycerol concentrations were increased (P<0.01) similarly in all three groups during exercise. In a separate experiment conducted in isolated hepatocytes from 24 h fasted Lou/C and Wistar rats, it was found that gluconeogenic flux from glycerol was found to be significantly (P<0.01) higher in Lou/C than in Wistar rats (5.4±0.2 vs 3.7±0.1 mumol/min/g dry cells). Resting and exercising plasma leptin levels were also significantly (P<0.05) lower in Lou/C than in the two other groups. CONCLUSION: It is concluded that Lou/C rats have the particularity to rely spontaneously less on their liver glycogen stores to meet their energy demands during exercise while maintaining euglycemia
Leanness of Lou/C rats does not require higher thermogenic capacity of brown adipose tissue
No full textInternational audienceLou/C rats, an inbred strain of Wistar origin, remain lean throughout life and therefore represent a remarkable model of obesity resistance. To date, the exact mechanisms responsible for the leanness of Lou/C rats remain unknown. The aim of the present study was to investigate whether the leanness of Lou/C rats relies on increased thermogenic capacities in brown adipose tissue (BAT). Results showed that although daily energy expenditure was higher in Lou/C than in Wistar rats, BAT thermogenic capacity was not enhanced in Lou/C rats kept at thermoneutrality as demonstrated by reduced thermogenic response to norepinephrine in vivo, similar oxidative activity of BAT isolated mitochondria in vitro, similar levels of UCP1 mRNA and lower abundance of UCP1 protein in interscapular BAT depots. Relative abundance of beta(3)-adrenergic receptor mRNA was lower in Lou/C BAT while that of GLUT4. FABP or CPT1 was not altered. Activity-related energy expenditure was however considerably increased at thermoneutrality as Lou/C rats demonstrated an impressively high spontaneous running activity in voluntary running wheels. Prolonged cold-exposure (4 degrees C) depressed the spontaneous running activity of Lou/C rats while BAT thermogenic capacity was increased as reflected by rises in BAT mass, oxidative activity and UCP1 expression. It is concluded that the leanness of Lou/C rats cannot be ascribed to higher thermogenic capacity of brown fat but rather to, at least in part, increased locomotor activity. BAT is not deficient in this rat strain as it can be stimulated by cold exposure when locomotor activity is reduced suggesting some substitution between these thermogenic processes. (C) 2011 Elsevier Inc. All rights reserved
Original regulation of energy balance in lean Lou/C rats : a model of hyperactivity and resistance to obesity
No full textLe rat Lou/C, issu de la souche Wistar, reste maigre tout au long de sa vie. Le but de ce travail était de caractériser la balance énergétique du rat Lou/C et d’établir quel(s) étai(en)t le(s) tissu(s) thermogène(s) impliqué(s) dans la dissipation de l’énergie alimentaire ingérée en excès. Si la quantité d’énergie ingérée, rapportée par unité de masse corporelle, n’était pas différente entre les deux souches de rats, la dépense énergétique du Lou/C était supérieure au repos, suite à un repas et lors de l’exercice physique. Le rat Lou/C montrait également une hyperactivité locomotrice spontanée volontaire bien supérieure à celle du Wistar. De façon inattendue, le tissu adipeux brun (BAT) des Lou/C était peu actif, comme l'ont montré des approches fonctionnelles in vivo, biochimiques in vitro ou moléculaires. L'absence d'activation du BAT du rat Lou/C n’était pas liée à une déficience du tissu puisqu’il était aisément activable par une exposition prolongée au froid. La forte activité physique spontanée du Lou/C ne s’accompagnait pas de l’activation de processus thermogènes particuliers des mitochondries isolées de BAT ou de muscle squelettique. En revanche, nous avons mis en évidence un mécanisme potentiel de découplage des oxydations phosphorylantes mitochondriales dans le foie des Lou/C. Contre toute attente, le rat Lou/C disposait de capacités de synthèse des acides gras équivalentes à celles du Wistar dans le foie et supérieures dans le tissu adipeux blanc avec de fortes capacités d’oxydation de ces substrats dans ces tissus, suggérant un possible cycle futile entre la synthèse des acides gras et leur oxydation dans le foie et le tissu adipeux blanc. Le rat Lou/C représente donc un modèle original de régulation de la balance énergétique qui n’est pas basé sur l’activité thermogène du BAT. Le muscle squelettique, le foie et le tissu adipeux blanc du Lou/C pourraient participer à un métabolisme actif des lipides et contribuer à la dissipation accrue de l’énergie ingérée en excès.Lou/C rat, an inbred strain of Wistar origin, remains lean throughout life. Our study aimed to characterize the energy balance of Lou/C rats and determine the tissue(s) that could be implicated in the dissipation of excess energy intake. Food intake, expressed per unit body mass, was not different between the two strains of rats but resting metabolic rate, diet-induced thermogenesis and exercise-associated energy expenditure were higher in the Lou/C strain. Moreover, the spontaneous activity of Lou/C rats was amazingly higher than that of Wistar rats. Unexpectedly, the thermogenic brown adipose tissue (BAT) of Lou/C rats was not over-stimulated as demonstrated by functional in vivo, biochemical in vitro or molecular approaches. Nevertheless, Lou/C BAT was not deficient as it could easily be stimulated by prolonged cold exposure. The high spontaneous activity of Lou/C rats was not correlated with an activation of specific thermogenic processes in isolated mitochondria of BAT or skeletal muscle. However, oxidation and phosphorylation were partly uncoupled in liver mitochondria of Lou/C rats. Unexpectedly, Lou/C rats displayed similar capacities for fatty acid synthesis in liver but higher capacities in white adipose tissue than Wistar rats, in association with high capacities for oxidation of these substrates in these tissues. These results suggested a possible mechanism of futile cycling between fatty acid synthesis and oxidation in liver and white adipose tissue. Lou/C rats therefore represent an original model of regulation of energy balance that is not based on the thermogenic activity of BAT. Skeletal muscle, liver and white adipose tissue of Lou/C rats could contribute to a higher lipid metabolism and the dissipation of excess energy intake
Régulation originale de la balance énergétique du rat Lou/C : un modèle d’hyperactivité et de résistance à l’obésité
No full textLou/C rat, an inbred strain of Wistar origin, remains lean throughout life. Our study aimed to characterize the energy balance of Lou/C rats and determine the tissue(s) that could be implicated in the dissipation of excess energy intake. Food intake, expressed per unit body mass, was not different between the two strains of rats but resting metabolic rate, diet-induced thermogenesis and exercise-associated energy expenditure were higher in the Lou/C strain. Moreover, the spontaneous activity of Lou/C rats was amazingly higher than that of Wistar rats. Unexpectedly, the thermogenic brown adipose tissue (BAT) of Lou/C rats was not over-stimulated as demonstrated by functional in vivo, biochemical in vitro or molecular approaches. Nevertheless, Lou/C BAT was not deficient as it could easily be stimulated by prolonged cold exposure. The high spontaneous activity of Lou/C rats was not correlated with an activation of specific thermogenic processes in isolated mitochondria of BAT or skeletal muscle. However, oxidation and phosphorylation were partly uncoupled in liver mitochondria of Lou/C rats. Unexpectedly, Lou/C rats displayed similar capacities for fatty acid synthesis in liver but higher capacities in white adipose tissue than Wistar rats, in association with high capacities for oxidation of these substrates in these tissues. These results suggested a possible mechanism of futile cycling between fatty acid synthesis and oxidation in liver and white adipose tissue. Lou/C rats therefore represent an original model of regulation of energy balance that is not based on the thermogenic activity of BAT. Skeletal muscle, liver and white adipose tissue of Lou/C rats could contribute to a higher lipid metabolism and the dissipation of excess energy intake.Le rat Lou/C, issu de la souche Wistar, reste maigre tout au long de sa vie. Le but de ce travail était de caractériser la balance énergétique du rat Lou/C et d’établir quel(s) étai(en)t le(s) tissu(s) thermogène(s) impliqué(s) dans la dissipation de l’énergie alimentaire ingérée en excès. Si la quantité d’énergie ingérée, rapportée par unité de masse corporelle, n’était pas différente entre les deux souches de rats, la dépense énergétique du Lou/C était supérieure au repos, suite à un repas et lors de l’exercice physique. Le rat Lou/C montrait également une hyperactivité locomotrice spontanée volontaire bien supérieure à celle du Wistar. De façon inattendue, le tissu adipeux brun (BAT) des Lou/C était peu actif, comme l'ont montré des approches fonctionnelles in vivo, biochimiques in vitro ou moléculaires. L'absence d'activation du BAT du rat Lou/C n’était pas liée à une déficience du tissu puisqu’il était aisément activable par une exposition prolongée au froid. La forte activité physique spontanée du Lou/C ne s’accompagnait pas de l’activation de processus thermogènes particuliers des mitochondries isolées de BAT ou de muscle squelettique. En revanche, nous avons mis en évidence un mécanisme potentiel de découplage des oxydations phosphorylantes mitochondriales dans le foie des Lou/C. Contre toute attente, le rat Lou/C disposait de capacités de synthèse des acides gras équivalentes à celles du Wistar dans le foie et supérieures dans le tissu adipeux blanc avec de fortes capacités d’oxydation de ces substrats dans ces tissus, suggérant un possible cycle futile entre la synthèse des acides gras et leur oxydation dans le foie et le tissu adipeux blanc. Le rat Lou/C représente donc un modèle original de régulation de la balance énergétique qui n’est pas basé sur l’activité thermogène du BAT. Le muscle squelettique, le foie et le tissu adipeux blanc du Lou/C pourraient participer à un métabolisme actif des lipides et contribuer à la dissipation accrue de l’énergie ingérée en excès
Vitamin A regulates hypothalamic–pituitary–adrenal axis status in LOU/C rats
No full textChantier qualité GAInternational audienceThe aim of this study was to explore the involvement of retinoids in the hypoactivity and hyporeactivity to stress of the hypothalamic–pituitary–adrenal (HPA) axis in LOU/C rats. We measured the effects of vitamin A deficiency administered or not with retinoic acid (RA) on plasma corticosterone in standard conditions and in response to restraint stress and on hypothalamic and hippocampal expression of corticosteroid receptors, corticotropin-releasing hormone and 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) in LOU/C rats. Interestingly, under control conditions, we measured a higher plasma concentration of retinol in LOU/C than in Wistar rats, which could contribute to the lower basal activity of the HPA axis in LOU/C rats. Vitamin A deficiency induced an increased HPA axis activity in LOU/C rats, normalized by RA administration. Compared with LOU/C control rats, vitamin A-deficient rats showed a delayed and heightened corticosterone response to restraint stress. The expression of corticosteroid receptors was strongly decreased by vitamin A deficiency in the hippocampus, which could contribute to a less efficient feedback by corticosterone on HPA axis tone. The expression of 11β-HSD1 was increased by vitamin A deficiency in the hypothalamus (+62.5%) as in the hippocampus (+104.7%), which could lead to a higher production of corticosterone locally and contribute to alteration of the hippocampus. RA supplementation treatment restored corticosterone concentrations and 11β-HSD1 expression to control levels. The high vitamin A status of LOU/C rats could contribute to their low HPA axis activity/reactivity and to a protective effect against 11β-HSD1-mediated deleterious action on cognitive performances during ageing
Etude du Lou/C, un rat résistant à l"obésité (contrôle de la prise alimentaire par l'AMPK hypothalamique, augmentation du métabolisme hépatique du glycérol, phénocopie partielle du Lou/C par un traitement chronique à la diiodothyronine)
No full textLe travail décrit dans ce manuscrit s'intéresse à la résistance à l'obésité et a eu pour objectif d'étudier les particularités métaboliques du rat Lou/C, une souche résistante à l'obésité. Dans un premier temps, notre travail a consisté à déterminer si l'hypophagie spontanée du Lou/C était liée à une modification de la voie de contrôle de la prise alimentaire dépendante de l'AMPK hypothalamique. Nos résultats montrent que le jeûne n'active pas l'AMPK hypothalamique chez le Lou/C, alors qu'il le fait chez le rat témoin. Cette observation pourrait expliquer, au moins en partie, la faible prise alimentaire du Lou/C. La deuxième partie de ce travail porte sur le métabolisme énergétique hépatique. En comparaison au rat témoin, nous avons montré que les hépatocytes de Lou/C avaient une plus grande capacité à métaboliser le glycérol, reflétant une gestion des potentiels d'oxydo-réduction différente. En effet, une augmentation de l'activité de la G3PdH mitochondriale permet au Lou/C de maintenir une cellule hépatique plus oxydée, et d'oxyder plus d'acides gras. Dans la troisième partie, nous présentons les résultats concernant les effets d'un traitement chronique à la diiodothyronine sur le phénotype et le métabolisme énergétique hépatique de rats témoins. Ce traitement induit des changements qui miment le phénotype du rat Lou/C : une stabilisation de la masse corporelle, un cytosol et une mitochondrie plus oxydés associés à une augmentation de l'activité et de l'expression de la G3PdH mitochondriale, une augmentation des capacités oxydatives mitochondriales. L'ensemble de ces données suggère que la T2 pourrait être impliquée dans le phénotype du rat résistant à l'obésité, Lou/e.The work reported here aimed at studying the phenotypical and metabolic characteristics of the Lou/C rat, a strain resistant to obesity. ln the first part, we studied whether the spontaneous hypophagia of Lou/C rats could be related to alterations of the hypothalamic AMPK pathway that controls food intake. Our results showed that starvation did not activate hypothalamic AMPK in Lou/C rats whereas it did in control rats. This observation could explain, at least partly, the lower food intake of Lou/C. The second part of our work deals with hepatic energy metabolism. Compared with control rats, the Ii vers of Lou/C rats were found to have a greater capacity to use glycerol, which reflected a different redox management. This could result from a higher content and activity of the mitochondrial G3PdH, which allow Lou/C rats to keep a more oxidized state and to enhance the rate offatty acid oxidation. The last part ofthis manuscript presents our results concerning the effects of a chronic 3,5 diiodothyronine (T2) treatment on the phenotype and hepatic energy metabolism of control rats. This treatment induced, in control rats, metabolic changes that mimicked to sorne extent the phenotype of Lou/C rats: their body weight was stable, their cytosol and mitochondria redox state were more oxidized and corresponded to a higher content and activity of the mitochondrial G3PdH, their mitochondria had enhanced oxidative capacities. Taken together our results suggest that T2 might be implicated in the peculiar phenotype of the resistant to obesity Lou/C rats.GRENOBLE1-BU Sciences (384212103) / SudocSudocFranceF
Le rat Lou/C anti-obèse dans l’ischémie/reperfusion cardiaque
No full textposter commenté session 04: Tissu adipeux, obésité, apnée du sommeilNational audienceLe rat lou/c constitue un excellent modèle de restriction calorique spontanée avec un poids corporel assez stable au cours de sa vie. Cette étude a visé à comparer la résistance cardiaque à l’ischémie/ reperfusion de ces rats à celle des rats Wistar qui deviennent obèses en vieillissant. Des cœurs des animaux des 2 souches ont été perfusés selon langendorff, puis soumis à une ischémie globale totale (25 min) suivie de reperfusion (30 min) après une période de stabilisation de 30 min. Chez les rats lou/c, la tolérance au glucose est supérieure. A la fin de la période de stabilisation, le travail mécanique des cœurs est nettement plus élevé grâce à un débit coronaire et une efficacité métabolique cardiaque plus importants. pendant la phase d’ischémie, la contracture est plus faible. a la reperfusion, la pression diastolique reste plus basse et la récupération contractile du myocarde est accrue. L’amélioration du fonctionnement cardiaque tout au long de la perfusion est associée à une participation plus importante du métabolisme oxydatif par rapport au métabolisme anaérobie (rapport entre la consommation d’oxygène et la production de lactate plus élevé). Ainsi, le volume vasculaire plus élevé des rats lou/c améliore le fonctionnement cardiaque en accroissant l’apport en oxygène dans les phases de normoxie et en augmentant la quantité résiduelle d’oxygène pendant l’ischémie. L’accroissement de la perfusion coronaire pourrait résulter d’une sensibilité à l’insuline plus élevé
Delayed age-associated decrease in growth hormone pulsatile secretion and increased orexigenic peptide expression in the Lou C/JaLL rat.
No full textInternational audienceSince modifications in the growth hormone/insulin-like growth factor 1 (GH/IGF-1) axis and/or caloric restriction are involved in the ageing process, GH secretory profiles, total IGF-1, ghrelin, and leptin plasma levels and expression of genes implicated in somatotrope axis and food intake regulation in hypothalamus and pituitary were compared in 3-, 12-, and 24-month-old male Lou C/Jall rats and their parent strain, the Wistar rats. The Lou C/Jall strain may appear as a healthy ageing model, since it does not become obese with age and maintains its caloric intake at 2 years of age. The GH pulsatile secretion decreased from 3 months in Wistar, but only after 12 months in Lou C/Jall rats. The IGF-1 levels were lower in Lou C/Jall rats and decreased more steeply with ageing as compared with Wistar rats. The total ghrelin levels were higher in young Lou C/Jall rats than in Wistar rats, but increased similarly with age in both strains. The leptin concentrations increased with ageing only in Wistar rats. By semiquantitative reverse-transcription polymerase chain reaction, pituitary GH secretagogue receptors and GH mRNA levels were more abundant in Lou C/Jall rats, and the latter decreased with ageing in Wistar rats only. Hypothalamic growth-hormone-releasing hormone and GH secretagogue receptor mRNA levels were similar in both strains and transiently increased only in middle-aged Wistar rats. Agouti-related peptide, neuropeptide Y, and orexin mRNA levels were more abundant in the Lou C/Jall rat hypothalamus, and the two former tended to further increase with age only in this strain. Conversely, the hypothalamic pro-opiomelanocortin mRNA levels were higher in old Wistar rats. In conclusion, ageing in Lou C/Jall rats is associated with a delayed decrease in pulsatile GH secretion in the presence of a lower IGF-1 tone and an increase in the expression of orexigenic neuropeptides in the hypothalamus
Improved leptin sensitivity as a potential candidate responsible for the spontaneous food restriction of the Lou/C rat.
No full textThe Lou/C rat, an inbred strain of Wistar origin, was described as a model of resistance to age- and diet-induced obesity. Although such a resistance involves many metabolic parameters described in our previous studies, Lou/C rats also exhibit a spontaneous food restriction due to decreased food consumption during the nocturnal period. We then attempted to delineate the leptin sensitivity and mechanisms implicated in this strain, using different protocols of acute central and peripheral leptin administration. A first analysis of the meal patterns revealed that Lou/C rats eat smaller meals, without any change in meal number compared to age-matched Wistar animals. Although the expression of the recognized leptin transporters (leptin receptors and megalin) measured in the choroid plexus was normal in Lou/C rats, the decreased triglyceridemia observed in these animals is compatible with an increased leptin transport across the blood brain barrier. Improved hypothalamic leptin signaling in Lou/C rats was also suggested by the higher pSTAT3/STAT3 (signal transducer and activator of transcription 3) ratio observed following acute peripheral leptin administration, as well as by the lower hypothalamic mRNA expression of the suppressor of cytokine signaling 3 (SOCS3), known to downregulate leptin signaling. To conclude, spontaneous hypophagia of Lou/C rats appears to be related to improved leptin sensitivity. The main mechanism underlying such a phenomenon consists in improved leptin signaling through the Ob-Rb leptin receptor isoform, which seems to consequently lead to overexpression of brain-derived neurotrophic factor (BDNF) and thyrotropin-releasing hormone (TRH)
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