Neuregulin 1 affects leptin levels, food intake and weight gain in normal-weight, but not obese, db/db mice

Aim. - Studies in vitro have highlighted the potential involvement of neuregulin 1 (NRG1) in the regulation of energy metabolism. This effect has also been suggested in vivo, as intracerebroventricular injection of NRG1 reduces food intakes and weight gain in rodents. Thus, it was hypothesised that NRG1 might affect serum leptin levels in mice. Methods. - Weight, food intakes, energy expenditure, spontaneous physical activity and serum leptin levels were evaluated in normal-weight C57BL/6JRJ mice following intraperitoneal administration of NRG1 (50 mu g/kg, three times/week) or saline for 8 weeks. Based on the results of this first experiment, leptin-resistant obese db/db mice were then given NRG1 for 8 weeks. Results. - Leptin serum concentrations were six times higher in C57BL/6JRJ mice treated with NRG1 than in the animals given saline. NRG1 treatment also reduced weight gain by 10% and food intakes by 15% compared with saline treatment, while energy expenditure remained unchanged. In db/db mice, serum leptin concentrations, weight gain, food intakes, energy expenditure and spontaneous physical activity were not altered by NRG1 treatment. Conclusion. - The decrease in food intakes and weight gain associated with NRG1 treatment in C57BL/6JRJ mice may be partly explained by increased leptin levels, whereas db/db mice were not affected by the treatment, suggesting resistance to NRG1 in this pathological state

Effets de deux modalités d'entraînement et d'une complémentation à base d'extraits végétaux sur le développement du diabète de type 2 : Physiologie

Type 2 diabetes (T2D) represents one of the main challenges for the 21 st century. In 2015, 415 million people in the world were diabetic and 318 million more showed signs of prediabetes, a condition defined by a high risk of developing T2D, though still reversible. Lifestyle recommendations (physical activity and diet) form the first line of intervention for T2D prevention. The objective of this thesis was to measure the effects of two lifestyle-based therapeutic strategies on T2D development. Study 1 aimed at comparing the effects of two chronic exercise modalities (moderate-intensity continuous training vs. high-intensity interval training) on the progression of T2D of young db/db mice. Study 2 was focused on assessing the effects of a blend of 5 plants (patented formula Totum-63) on the development of T2D of two murine models of prediabetes: young db/db mice and high-fat diet induced insulin resistance mice. In study 1, high-intensity interval training improved glycaemic control maybe through enhanced muscular Glut4 content despite no adaptation of mitochondrial function. In study 2, Totum-63 supplementation improved glycaemic control and insulin sensitivity in both models of prediabetes. Several mechanisms in tissues involved in T2D physiopathology were unveiled, suggesting a pleiotropic action of Totum-63. In conclusion, this work supports the interest of these two lifestyle- based interventions for preventing T2D development. Future prospects include the study of the combined action of chronic exercise and Totum-63.Le diabète de type 2 (DT2) représente l’un des principaux défis de santé du XXI ème siècle. En 2015, 415 millions de personnes dans le monde étaient touchées tandis que 318 millions de plus présentaient un prédiabète, un stade défini comme à haut risque de développer la pathologie, mais encore réversible. Les recommandations hygiéno-diététiques (activité physique et alimentation) constituent la première ligne d’intervention dans le cadre de la lutte contre l’apparition du diabète de type 2. L’objectif de cette thèse était d'évaluer l’effet de deux stratégies interventionnelles inscrites dans les mesures hygiéno-diététiques sur le développement du DT2. L’étude 1 visait à comparer l’effet de deux modalités d’exercice chronique (continu à intensité modérée vs. intermittent de haute intensité) sur le développement du DT2 de jeunes souris db/db. L’étude 2 s’attachait à mesurer les effets d’un mélange de 5 extraits de plantes (Composition brevetée Totum-63,) sur le développement du DT2 à partir de deux modèles du prédiabète : la jeune souris db/db et la souris rendue insulinorésistante suite à un régime riche en graisses. Dans la 1 ère étude, l’entrainement intermittent de haute intensité a amélioré le contrôle glycémique indépendamment d’une adaptation de la fonction mitochondriale via notamment une augmentation du contenu musculaire en Glut4. Dans notre seconde étude, Totum- 63 a entrainé une amélioration du contrôle glycémique et de la sensibilité à l’insuline dans nos deux modèles. Plusieurs mécanismes sur différents tissus impliqués dans la physiopathologie du DT2 ont été mis en évidence, suggérant une action pléiotrope de Totum-63. En conclusion, ces résultats soutiennent l’intérêt de ces deux approches non-médicamenteuses dans le cadre de la lutte contre le développement du DT2. L’étude de l’action de l’activité physique combinée à celle de Totum-63, présente un intérêt supplémentaire et constitue un prolongement possible des travaux de cette thèse

Effect of two chronic exercise modalities and of a 5 plants blend on the development of Type 2 diabetes

Le diabète de type 2 (DT2) représente l’un des principaux défis de santé du XXI ème siècle. En 2015, 415 millions de personnes dans le monde étaient touchées tandis que 318 millions de plus présentaient un prédiabète, un stade défini comme à haut risque de développer la pathologie, mais encore réversible. Les recommandations hygiéno-diététiques (activité physique et alimentation) constituent la première ligne d’intervention dans le cadre de la lutte contre l’apparition du diabète de type 2. L’objectif de cette thèse était d'évaluer l’effet de deux stratégies interventionnelles inscrites dans les mesures hygiéno-diététiques sur le développement du DT2. L’étude 1 visait à comparer l’effet de deux modalités d’exercice chronique (continu à intensité modérée vs. intermittent de haute intensité) sur le développement du DT2 de jeunes souris db/db. L’étude 2 s’attachait à mesurer les effets d’un mélange de 5 extraits de plantes (Composition brevetée Totum-63,) sur le développement du DT2 à partir de deux modèles du prédiabète : la jeune souris db/db et la souris rendue insulinorésistante suite à un régime riche en graisses. Dans la 1 ère étude, l’entrainement intermittent de haute intensité a amélioré le contrôle glycémique indépendamment d’une adaptation de la fonction mitochondriale via notamment une augmentation du contenu musculaire en Glut4. Dans notre seconde étude, Totum- 63 a entrainé une amélioration du contrôle glycémique et de la sensibilité à l’insuline dans nos deux modèles. Plusieurs mécanismes sur différents tissus impliqués dans la physiopathologie du DT2 ont été mis en évidence, suggérant une action pléiotrope de Totum-63. En conclusion, ces résultats soutiennent l’intérêt de ces deux approches non-médicamenteuses dans le cadre de la lutte contre le développement du DT2. L’étude de l’action de l’activité physique combinée à celle de Totum-63, présente un intérêt supplémentaire et constitue un prolongement possible des travaux de cette thèse.Type 2 diabetes (T2D) represents one of the main challenges for the 21 st century. In 2015, 415 million people in the world were diabetic and 318 million more showed signs of prediabetes, a condition defined by a high risk of developing T2D, though still reversible. Lifestyle recommendations (physical activity and diet) form the first line of intervention for T2D prevention. The objective of this thesis was to measure the effects of two lifestyle-based therapeutic strategies on T2D development. Study 1 aimed at comparing the effects of two chronic exercise modalities (moderate-intensity continuous training vs. high-intensity interval training) on the progression of T2D of young db/db mice. Study 2 was focused on assessing the effects of a blend of 5 plants (patented formula Totum-63) on the development of T2D of two murine models of prediabetes: young db/db mice and high-fat diet induced insulin resistance mice. In study 1, high-intensity interval training improved glycaemic control maybe through enhanced muscular Glut4 content despite no adaptation of mitochondrial function. In study 2, Totum-63 supplementation improved glycaemic control and insulin sensitivity in both models of prediabetes. Several mechanisms in tissues involved in T2D physiopathology were unveiled, suggesting a pleiotropic action of Totum-63. In conclusion, this work supports the interest of these two lifestyle- based interventions for preventing T2D development. Future prospects include the study of the combined action of chronic exercise and Totum-63

Neuregulin 1 Improves Glucose Tolerance in db/db Mice.

In vitro experiments using rodent skeletal muscle cells suggest that neuregulin 1 (NRG1) is involved in glucose metabolism regulation, although no study has evaluated the role of NRG1 in systemic glucose homeostasis. The purpose of this study was to investigate the effect of chronic and acute NRG1 treatment on glucose homeostasis in db/db mice. To this aim, glucose tolerance tests were performed in 8-week-old male db/db mice after treatment with NRG1 (50μg.kg-1) or saline 3 times per week for 8 weeks. In other experiments, glucose tolerance and pyruvate tolerance tests were performed in db/db mice 15 minutes after a single NRG1 (50μg.kg-1) or saline injection. Liver, adipose tissue, hypothalamus and skeletal muscle were also collected 30 minutes after acute NRG1 (50μg.kg-1) or saline treatment, and the phosphorylation status of the ERBB receptors, AKT (on Ser473) and FOXO1 (on Ser256) was assessed by western blotting. Chronic treatment (8 weeks) with NRG1 improved glucose tolerance in db/db mice. Acute treatment also lowered glycemia and insulinemia during glucose or pyruvate tolerance tests. NRG1 acute injection induced activation of ERBB3 receptors and phosphorylation of AKT and FOXO1 only in liver. Altogether, this study shows that acute and chronic NRG1 treatments improve glucose tolerance in db/db mice. This effect could be mediated through inhibition of hepatic gluconeogenesis

Comparison of Oxygen Consumption in Rats during Uphill (Concentric) and Downhill (Eccentric) Treadmill Exercise Tests

Times Cited: 0International audienceThe study of the physiological adaptations of skeletal muscle in response to eccentric (ECC) contraction is based on protocols in which exercise intensities are determined relative to the concentric (CON) reference exercise (as percentage of the CON maximal oxygen consumption, or VO2max). In order to use similar exercise protocols in rats, we compared the VO2 values during uphill (CON) and downhill (ECC) running tests. VO2 was measured in 15 Wistar rats during incremental treadmill running exercises with different slopes: level (0%), positive (+15% incline: CON+15%) and negative (-15% incline: ECC-15%; and -30% incline: ECC-30%). Similar VO2 values were obtained in the ECC-30% and CON+15% running conditions at the three target speeds (15, 25 and 35 cm/sec). Conversely, VO2 values were lower (p < 0.05) in the ECC-15% than in the CON+15% condition (CON+15% VO2/ECC-15% VO2 ratios ranging from 1.86 to 2.05 at the three target speeds). Thus, doubling the downhill slope gradient in ECC condition leads to an oxygen consumption level that is not significantly different as in CON condition. These findings can be useful for designing animal research protocols to study the effects of ECC and CON exercise in ageing population or subjects suffering from cardiovascular diseases

Neuregulin 1 improves complex 2-mediated mitochondrial respiration in skeletal muscle of healthy and diabetic mice

It has been reported that neuregulin1 (NRG1) improves glucose tolerance in healthy and diabetic rodents. In vitro studies also suggest that NRG1 regulates myocyte oxidative capacity. To confirm this observation in vivo, we evaluated the effect on mitochondrial function of an 8-week treatment with NRG1 in db/db diabetic mice and C57BL/6JRJ healthy controls. NRG1 treatment improved complex 2-mediated mitochondrial respiration in the gastrocnemius of both control and diabetic mice and increased mitochondrial complex 2 subunit content by 2-fold. This effect was not associated with an increase in mitochondrial biogenesis markers. Enhanced ERBB4 phosphorylation could mediate NRG1 effects on mitochondrial function through signalling pathways, independently of ERK1/2, AKT or AMP

High intensity interval training improves glucose metabolism in diabetic mice despite limited mitochondrial adaptations

National audienceRecent studies have proved in patients with type 2 diabetes the positive effects of High Intensity Interval Training (HIIT) programs on hyperglycemia and muscle mitochondrial capacity. The aim of this work was to compare the effects of HIIT with a traditional Moderate Intensity Continuous Training (MICT) on glucose metabolism and mitochondrial function in diabetic mice. 25 db/db mice aged 6 weeks were subdivided into MICT group, HIIT group, or control group (CON). Animals in the training groups ran on a treadmill 5 days/week during 10 weeks. In vivo, ex vivo and post-mortem biochemical measurements were performed at the end at the end of the protocol. HIIT lowered fasting glycemia (-40% vs CON) and HbA1c (-20% vs CON), and improved response to starch and insulin tolerance tests vs CON group. No changes were noted in MICT group regarding the glucose homeostasis. 24h respiratory exchange ratio was increased in HIIT (+6% vs CON) and MICT group (+4% vs CON) after the training program but without any changes in 24h total energy expenditure. ETC protein content was increased in HIIT vs CON, whereas other mitochondrial density markers were unchanged. Western blot analysis revealed a significant increase of muscle Glut4 content and higher Akt phosphorylation ratios only in HIIT group. This study showed that HIIT may improve glucose metabolism more efficiently than traditional MICT in diabetic mice by mechanisms independent of mitochondrial adaptations. As already reported in the literature, intact leptin signaling might be necessary for exercise-induced adaptation of mitochondrial function through AMPK and Sirt1 in the muscl

High intensity interval training improves glucose metabolism in diabetic mice despite limited mitochondrial adaptations

National audienceRecent studies have proved in patients with type 2 diabetes the positive effects of High Intensity Interval Training (HIIT) programs on hyperglycemia and muscle mitochondrial capacity. The aim of this work was to compare the effects of HIIT with a traditional Moderate Intensity Continuous Training (MICT) on glucose metabolism and mitochondrial function in diabetic mice. 25 db/db mice aged 6 weeks were subdivided into MICT group, HIIT group, or control group (CON). Animals in the training groups ran on a treadmill 5 days/week during 10 weeks. In vivo, ex vivo and post-mortem biochemical measurements were performed at the end at the end of the protocol. HIIT lowered fasting glycemia (-40% vs CON) and HbA1c (-20% vs CON), and improved response to starch and insulin tolerance tests vs CON group. No changes were noted in MICT group regarding the glucose homeostasis. 24h respiratory exchange ratio was increased in HIIT (+6% vs CON) and MICT group (+4% vs CON) after the training program but without any changes in 24h total energy expenditure. ETC protein content was increased in HIIT vs CON, whereas other mitochondrial density markers were unchanged. Western blot analysis revealed a significant increase of muscle Glut4 content and higher Akt phosphorylation ratios only in HIIT group. This study showed that HIIT may improve glucose metabolism more efficiently than traditional MICT in diabetic mice by mechanisms independent of mitochondrial adaptations. As already reported in the literature, intact leptin signaling might be necessary for exercise-induced adaptation of mitochondrial function through AMPK and Sirt1 in the muscl

High intensity interval training improves glucose homeostasis in diabetic db/db mice

International audienc

Effects of high-intensity interval training and moderate-intensity continuous training on glycaemic control and skeletal muscle mitochondrial function in db/db mice

The authors wish to thank Mr Mehdi Djelloul-Mazouz and Mr Philippe Denis from INRA Unité de Nutrition Humaine (UNH, UMR 1019), CRNH Auvergne (France) for the care and the attention to the animals. We also thank Mrs Monique Etienne from AME2P Lab (Clermont-Ferrand, France) and Mrs Anne-Sophie Galvardon for their excellent assistance during the experimentsInternational audiencePhysical activity is known as an effective strategy for prevention and treatment of Type 2 Diabetes. The aim of this work was to compare the effects of a traditional Moderate Intensity Continuous Training (MICT) with a High Intensity Interval Training (HIIT) on glucose metabolism and mitochondrial function in diabetic mice. Diabetic db/db male mice (N = 25) aged 6 weeks were subdivided into MICT, HIIT or control (CON) group. Animals in the training groups ran on a treadmill 5 days/week during 10 weeks. MICT group ran for 80 min (0 degrees slope) at 50-60% of maximal speed (Vmax) reached during an incremental test. HIIT group ran thirteen times 4 minutes (20 degrees slope) at 85-90% of Vmax separated by 2-min-rest periods. HIIT lowered fasting glycaemia and HbA1c compared with CON group (p < 0.05). In all mitochondrial function markers assessed, no differences were noted between the three groups except for total amount of electron transport chain proteins, slightly increased in the HIIT group vs CON. Western blot analysis revealed a significant increase of muscle Glut4 content (about 2 fold) and higher insulin-stimulated Akt phosphorylation ratios in HIIT group. HIIT seems to improve glucose metabolism more efficiently than MICT in diabetic mice by mechanisms independent of mitochondrial adaptation