RESUMEN
Obesity is a predictive factor for the development of nonalcoholic steatohepatitis (NASH). Although some of the mechanisms associated with NASH development are still elusive, its pathogenesis relies on a complex broad spectrum of (interconnected) metabolic-based disorders. We analyzed the effects of voluntary physical activity (VPA) and endurance training (ET), as preventive and therapeutic nonpharmacological strategies, respectively, against hepatic endoplasmic reticulum (ER) stress, ER-related proapoptotic signaling, and oxidative stress in an animal model of high-fat diet (HFD)-induced NASH. Adult male Sprague-Dawley rats were divided into standard control liquid diet (SCLD) or HFD groups, with sedentary, VPA, and ET subgroups in both (sedentary animals with access to SCLD [SS], voluntarily physically active animals with access to SCLD [SV], and endurance-trained animals with access to SCLD [ST] in the former and sedentary animals with access to liquid HFD [HS], voluntarily physically active animals with access to liquid HFD [HV], and endurance-trained animals with access to liquid HFD [HT] in the latter, respectively). Hepatic ER stress and ER-related proapoptotic signaling were evaluated by Western blot and reverse transcriptase-polymerase chain reaction; redox status was evaluated through quantification of lipid peroxidation, protein carbonyls groups, and glutathione levels as well as antioxidant enzymes activity. In SCLD-treated animals, VPA significantly decreased eukaryotic initiation factor-2 alpha (eIF2α). In HFD-treated animals, VPA significantly decreased eIF2α and phospho-inositol requiring enzyme-1 alpha (IRE1α) but ET significantly decreased eIF2α and significantly increased both spliced X-box binding protein 1 (sXBP1) and unspliced X-box binding protein 1; a significant increase of phosphorylated-eIF2α (p-eIF2α) to eIF2α ratio occurred in ET versus VPA. HS compared to SS disclosed a significant increase of total and reduced glutathione, HV compared to SV a significant increase of oxidized glutathione, HT compared to ST a significant increase of p-eIF2α to eIF2α ratio and sXBP1. Physical exercise counteracts NASH-related ER stress and its associated deleterious consequences through a positive and dynamical modulation of the hepatic IRE1α-X-box binding protein 1 pathway.
Asunto(s)
Enfermedad del Hígado Graso no Alcohólico , Animales , Masculino , Ratas , Estrés del Retículo Endoplásmico , Endorribonucleasas/metabolismo , Factor 2 Eucariótico de Iniciación/metabolismo , Enfermedad del Hígado Graso no Alcohólico/etiología , Enfermedad del Hígado Graso no Alcohólico/terapia , Enfermedad del Hígado Graso no Alcohólico/metabolismo , Proteínas Serina-Treonina Quinasas , Ratas Sprague-Dawley , Proteína 1 de Unión a la X-Box , Condicionamiento Físico AnimalRESUMEN
BACKGROUND/OBJECTIVES: The browning of white adipose tissue (WAT) has been in the spotlight during the last years, becoming an attractive approach to combat obesity. Melanocortin neuropeptides, such as α-melanocyte-stimulating hormone (α-MSH), are well-known regulators of appetite at the central nervous system, but its role in adipocyte metabolism is poorly elucidated. This study sought to verify if α-MSH can induce transdifferentiation of white to brown/beige adipocytes and to determine whether it can ameliorate the obesity phenotype. METHODS: The browning effect of α-MSH was determined in isolated adipocytes using the 3T3-L1 cell line and in inguinal subcutaneous adipose tissue (ingWAT) of diet-induced obese (DIO) mice by quantifying the expression of browning hallmark genes, oxygen consumption, and mitochondrial biogenesis. α-MSH protection from diet-induced obesity was evaluated by analyzing mice body weight, fat mass, and lipid and glucose serum profiles. RESULTS: Here, we report that α-MSH activates a thermogenic gene program and increases the mitochondrial respiratory rate in 3T3-L1 adipocytes and ingWAT of DIO mice. Without affecting food intake, peripheral administration of α-MSH decreases body weight and ingWAT mass, promoting a significant rise in the number of smaller adipocytes, whereas it lowered the larger ones. Additionally, there was an increase in the mass of brown adipose tissue. Browning activation occurs concomitantly with improvement on serum lipid profile, insulin resistance, and glucose homeostasis. CONCLUSIONS: This study highlights the anti-obesity properties of melanocortins by promoting ingWAT browning and provides new perspectives for future designing of more effective therapeutic strategies.
Asunto(s)
Adipocitos/metabolismo , Tejido Adiposo Beige/efectos de los fármacos , Tejido Adiposo Pardo/efectos de los fármacos , Tejido Adiposo Blanco/efectos de los fármacos , Melanocortinas/farmacología , Obesidad/prevención & control , Termogénesis/efectos de los fármacos , Células 3T3-L1 , Adipocitos/efectos de los fármacos , Tejido Adiposo Beige/metabolismo , Tejido Adiposo Pardo/metabolismo , Tejido Adiposo Blanco/metabolismo , Animales , Células Cultivadas , Dieta Alta en Grasa , Ratones , Ratones Endogámicos C57BL , Obesidad/metabolismo , Termogénesis/fisiologíaRESUMEN
The dysregulation of adipokine secretion owing to adiposopathy can contribute to the pathogenesis of obesity-related disorders. Being that exercise is an advised strategy against obesity-induced adiposopathy, we aimed to analyze the role of physical exercise as a preventive and therapeutic strategy against high-fat diet (HFD)-induced adipokine and ghrelin alterations. Rats were pair-fed the Lieber De Carli standard diet (S, 35 Kcal% fat) or HFD (71 Kcal% fat) over 17 weeks. Animals were assigned into four groups as follows: standard diet sedentary (SS), standard diet voluntary physical activity (SVPA), high-fat diet sedentary (HS), and high-fat diet voluntary physical activity (HVPA). After 9 weeks of dietary treatment, half of the SS and HS animals were submitted to an 8-week endurance training program, standard diet endurance training (SET), and high-fat-diet endurance training (HET) groups, maintaining the respective diets. Although there were no changes in body weight, HFD increased visceral adiposity, percentage of large adipocytes, hypoxia inducible factor (HIF)-1α, and leptin contents in epididymal adipose tissue (eWAT) and decreased plasma content of adiponectin (AdipQ). Both VPA and ET decreased visceral adiposity and percentage of large adipocytes in HFD-fed animals, but ET also increased the percentage of small- to medium-sized adipocytes. VPA increased plasma growth hormone secretagogue receptor (GHS-R) and decreased leptin protein in HVPA group. ET decreased plasma insulin and leptin levels and eWAT HIF-1α and leptin expression in HET group. Moreover, ET improved insulin sensitivity, plasma high molecular weight, and AdipQ and ghrelin levels and increased eWAT and GHS-R expression. Our data suggest that exercise, particularly ET, reverted adiposopathy and related endocrine alterations induced by an isocaloric HFD pair-fed diet.
Asunto(s)
Tejido Adiposo/patología , Dieta Alta en Grasa , Modelos Animales de Enfermedad , Sistema Endocrino/fisiopatología , Obesidad/prevención & control , Condicionamiento Físico Animal , Adiponectina/sangre , Tejido Adiposo/metabolismo , Animales , Peso Corporal , Ghrelina/sangre , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Insulina/sangre , Resistencia a la Insulina , Leptina/sangre , Masculino , Obesidad/etiología , Obesidad/metabolismo , Obesidad/fisiopatología , Ratas Sprague-Dawley , Receptores de Ghrelina/metabolismo , Factor A de Crecimiento Endotelial Vascular/metabolismoRESUMEN
PURPOSE: Autophagy and apoptosis play critical roles in both development and tissue homeostasis in response to (patho)physiological stimuli, such as high-fat diet (HFD) and endurance training (ET). Therefore, we aimed to investigate how ET modulates autophagy and apoptotic-related signaling in visceral adipose tissue of long-standing HFD-fed rats. METHODS: The study was conducted over a 17-week period on Sprague-Dawley rats, which were divided into four groups (n = 8/group): standard diet sedentary (STD+SED), high-fat diet sedentary (HFD+SED), standard diet ET (STD+ET) and high-fat diet ET (HFD+ET). After 9 weeks of dietary regimens, ET groups were trained for 8 weeks on treadmill (5 days/week at 25 m/min for 60 min/day), while maintaining dietary regimens. Autophagy and apoptotic-signaling markers in epididymal white adipose tissue (eWAT) were determined using RT-qPCR, Western blot and spectrometry techniques. RESULTS: ET reduced body weight, visceral fat mass and HOMA-IR in standard and HF diet-fed animals. Moreover, ET reverted the HFD-induced increases in the percentage of larger adipocytes and also reduced the percentage of smaller adipocytes. The HFD decreased pre-adipocyte factor 1 (DLK1/PREF1) and increased the pro-apoptotic markers (Bax protein and caspase 3-like activity), while having no impact on autophagy markers. However, ET increased DLK1/PREF1 and Bcl-2 in both diet types, while decreasing Bax and caspases 9, 8 and 3-like activities in HFD feeding rats. Additionally, Beclin-1 and p62 protein significantly increased in ET groups of both diet types. CONCLUSIONS: Data demonstrate that 8 weeks of ET was effective in attenuating apoptotic-related signaling in long-standing HFD-fed rats. Moreover, HFD and ET had no impact on VAT autophagy markers.
Asunto(s)
Tejido Adiposo/metabolismo , Autofagia , Dieta Alta en Grasa , Grasa Intraabdominal/metabolismo , Condicionamiento Físico Animal , Animales , Dieta Alta en Grasa/efectos adversos , Masculino , Obesidad , Ratas , Ratas Sprague-DawleyRESUMEN
PURPOSE: Studies associate specific fatty-acids (FA) with the pathophysiology of inflammation. We aimed to analyze the impact of exercise on adipose tissue FA profile in response to a high-fat diet (HFD) and to ascertain whether these exercise-induced changes in specific FA have repercussions on obesity-related inflammation. METHODS: Sprague-Dawley rats were assigned into sedentary, voluntary physical-activity (VPA) and endurance training (ET) groups fed a standard (S, 35kcal% fat) or high-fat (71kcal% fat) diets. VPA-animals had unrestricted access to wheel-running. After 9-wks, ET-animals engaged a running protocol for 8-wks, while maintained dietary treatments. The FA content in epididymal white-adipose tissue (eWAT) triglycerides was analyzed by gas-chromatography and the expression of inflammatory markers was determined using RT-qPCR, Western and slot blotting. RESULTS: Eight-wks of ET reversed obesity-related anatomical features. HFD increased plasma tumor necrosis factor (TNF)-α content and eWAT monocyte chemoattractant protein (MCP)-1 protein expression. HFD decreased eWAT content of saturated FA and monounsaturated FA, while increased linoleic acid and prostaglandin E2 (PGE2) levels in eWAT. VPA decreased visceral adiposity, adipocyte size and MCP-1 in HFD-fed animals. The VPA and ET interventions diminished palmitoleic acid and increased linoleic acid in HFD-fed groups. Moreover, both interventions increased PGE2 levels in standard diet-fed groups and decreased in HFD. ET increased eWAT fatty acid desaturase 1 (FADS1) and elongase 5 (ELOVL5) protein content in both diet types. ET reduced eWAT inflammatory markers (TNF-α, IL-6), macrophage recruitment (MCP-1 and F4/80) and increased IL-10/TNF-α ratio in plasma and in eWAT in both diet types. CONCLUSIONS: Exercise induced FA-specific changes independently of dietary FA composition, but only ET attenuated the inflammatory response in VAT of HFD-fed rats. Moreover, the exercise-induced FA changes did not correlate with the inflammatory response in VAT of rats submitted to HFD.
Asunto(s)
Dieta Alta en Grasa/efectos adversos , Ácidos Grasos/metabolismo , Grasa Intraabdominal/metabolismo , Condicionamiento Físico Animal , Adiposidad , Animales , Biomarcadores/metabolismo , Peso Corporal , Citocinas/metabolismo , Metabolismo Energético , Inflamación/metabolismo , Grasa Intraabdominal/citología , Masculino , Ratas , Ratas Sprague-DawleyRESUMEN
We aimed to investigate the effects of two physical exercise models, voluntary physical activity (VPA) and endurance training (ET) as preventive and therapeutic strategies, respectively, on lipid accumulation regulators and mitochondrial content in VAT of rats fed a high-fat diet (HFD). Sprague-Dawley rats (6 weeks old, n=60) were assigned into sedentary and VPA groups fed isoenergetic diets: standard (S, 35 kcal% fat) or HFD (71 kcal% fat). The VPA groups had free access to wheel running during the entire protocol. After 9 weeks, half of the sedentary animals were exercised on a treadmill while maintaining the dietary treatments. The HFD induced no changes in plasma non-esterified fatty acids (NEFA) and glycerol levels and decreased oxidative phosphorylation (OXPHOS) subunit IV and increased truncated/full-length sterol regulatory element-binding transcription factor 1c (SREBP1c) ratio in epididymal white adipose tissue (eWAT). VPA decreased plasma glycerol levels, aquaglyceroporin 7 (AQP7) and increased subunit I of cytochrome c oxidase (COX) protein, in standard diet fed animals. Eight weeks of ET decreased body weight, visceral adiposity and adipocyte size and plasma NEFA and glycerol levels, as well as AQP7 protein expression in eWAT. ET increased fatty acid translocase (FAT/CD36), mitochondrial content of complexes IV and V subunits, mitochondrial biogenesis and dynamic (mitofusins and optic atrophy 1)-related proteins. Moreover, lipogenesis-related markers (SREBP1c and acetyl CoA carboxylase) were reduced after 8 weeks of ET. In conclusion, ET-induced alterations reflect a positive effect on mitochondrial function and the overall VAT metabolism of HFD-induced obese rats.
Asunto(s)
Dieta Alta en Grasa , Grasa Intraabdominal/metabolismo , Metabolismo de los Lípidos , Mitocondrias/metabolismo , Actividad Motora/fisiología , Obesidad/metabolismo , Resistencia Física/fisiología , Tejido Adiposo Blanco/metabolismo , Adiposidad , Animales , Acuaporinas/metabolismo , Biomarcadores/metabolismo , Ácidos Grasos no Esterificados/sangre , Glicerol/sangre , Lipogénesis/fisiología , Masculino , Obesidad/sangre , Obesidad/prevención & control , Fosforilación Oxidativa , Ratas Sprague-Dawley , Proteína 1 de Unión a los Elementos Reguladores de Esteroles/metabolismoRESUMEN
AIMS: Exercise-stimulated myokine secretion into circulation may be related with browning in white adipose tissue (WAT), representing a positive metabolic effect on whole-body fat mass. However, limited information is yet available regarding the impact of exercise on myokine-related modulation of adipocyte phenotype in WAT from obese rats. MAIN METHODS: Sprague-Dawley rats (n=60) were divided into sedentary and voluntary physical activity (VPA) groups and fed with standard (35kcal% fat) or high-fat (HFD, 71kcal% fat)-isoenergetic diets. The VPA-groups had unrestricted access to wheel running throughout the protocol. After-9weeks, half of sedentary standard (SS) and sedentary HFD (HS)-fed animals were exercised on treadmill (endurance training, ET) for 8-weeks while maintaining the dietary treatments. KEY FINDINGS: The adipocyte hypertrophy induced by HFD were attenuated by VPA and ET. HFD decreased 5' AMP-activated protein kinase (AMPK) activity in muscle as well as peroxisome proliferator-activated receptor gamma coactivator-1α (PGC-1α) and uncoupling protein 1 (UCP1) proteins in eWAT, while not affecting circulating irisin. VPA increased eWAT Tmem26 mRNA levels in the standard diet-fed group, whereas ET increased AMPK, interleukin 6 (IL-6) and fibronectin type III domain-containing protein 5 (FNDC5) protein expression in muscle, but had no impact on circulating irisin protein content. In eWAT, ET increased bone morphogenetic protein 7 (Bmp7), Cidea and PGC-1α in both diet-fed animals, whereas BMP7, Prdm16, UCP1 and FNDC5 only in standard diet-fed group. SIGNIFICANCE: Data suggest that ET-induced myokine production seems to contribute, at least in part, to the "brown-like" phenotype in WAT from rats fed a HFD.
Asunto(s)
Tejido Adiposo Pardo/metabolismo , Citocinas/metabolismo , Dieta Alta en Grasa , Condicionamiento Físico Animal , Adiposidad , Animales , Peso Corporal , Metabolismo Energético , Masculino , Músculo Esquelético/metabolismo , Fenotipo , Ratas , Ratas Sprague-DawleyRESUMEN
Mitochondrial quality control and apoptosis have been described as key components in the pathogenesis of nonalcoholic steatohepatitis (NASH); exercise is recognized as a nonpharmacological strategy to counteract NASH-associated consequences. We aimed to analyze the effect of voluntary physical activity (VPA) and endurance training (ET) against NASH-induced mitochondrial permeability transition pore (mPTP) opening and mitochondrial and cellular quality control deleterious alterations. Forty-eight male Sprague-Dawley rats were divided into standard-diet sedentary (SS, n = 16), standard-diet VPA (n = 8), high-fat diet sedentary (HS, n = 16), and high-fat diet VPA (n = 8). After 9 weeks of diet treatment, half of the SS and HS groups were engaged in an ET program for 8 weeks, 5 days/week, 1 h/day. Liver mPTP susceptibility through osmotic swelling, mPTP-related proteins (cyclophilin D, Sirtuin3, Cofilin-1), markers of mitochondrial biogenesis ((mitochondrial transcription factor A (Tfam) and peroxisome proliferator-activated receptor gamma co-activator protein (PGC-1α)), dynamics (Mitofusin 1 (Mfn1), Mitofusin 2 (Mfn2), Dynamin related protein 1, and Optic atrophy 1)), auto/mitophagy (Beclin-1, microtubule-associated protein 1 light chain 3, p62, PINK1, and Parkin), and apoptotic signaling (Bax, Bcl-2) and caspases-like activities were assessed. HS animals showed an increased susceptibility to mPTP, compromised expression of Tfam, Mfn1, PINK1, and Parkin and an increase in Bax content (HS vs. SS). ET and VPA improved biogenesis-related proteins (PGC-1α) and autophagy signaling (Beclin-1 and Beclin-1/Bcl-2 ratio) and decreased apoptotic signaling (caspases 8 activity, Bax content, and Bax/Bcl-2 ratio). However, only ET decreased mPTP susceptibility and positively modulated Bcl-2, Tfam, Mfn1, Mfn2, PINK1, and Parkin content. In conclusion, exercise reduces the increased susceptibility to mPTP induced by NASH and promotes the increase of auto/mitophagy and mitochondrial fusion towards a protective phenotype.
Asunto(s)
Hígado/metabolismo , Potencial de la Membrana Mitocondrial , Proteínas de Transporte de Membrana Mitocondrial/metabolismo , Enfermedad del Hígado Graso no Alcohólico/prevención & control , Condicionamiento Físico Animal , Animales , Apoptosis , Proteínas Reguladoras de la Apoptosis/metabolismo , Dieta Alta en Grasa , Modelos Animales de Enfermedad , Hígado/patología , Masculino , Mitocondrias Hepáticas/metabolismo , Mitocondrias Hepáticas/patología , Dinámicas Mitocondriales , Poro de Transición de la Permeabilidad Mitocondrial , Dilatación Mitocondrial , Enfermedad del Hígado Graso no Alcohólico/metabolismo , Enfermedad del Hígado Graso no Alcohólico/patología , Resistencia Física , Ratas Sprague-Dawley , Conducta Sedentaria , Transducción de SeñalRESUMEN
BACKGROUND & AIMS: Lieber-DeCarli diet has been used to induce obesity and non-alcoholic steatohepatitis (NASH). As scarce anatomical and clinical-related information on this diet model exists and being exercise an advised strategy to counteract metabolic diseases, we aimed to analyze the preventive (voluntary physical activity - VPA) and therapeutic (endurance training - ET) effect of exercise on clinical/anatomical features of rats fed with Lieber-DeCarli diet. METHODS: In the beginning of the protocol, Sprague-Dawley rats were divided into standard-diet sedentary (SS, n = 20), standard-diet VPA (SVPA, n = 10), high-fat diet sedentary (HS, n = 20) and high-fat diet VPA (HVPA, n = 10) groups. After 9-weeks, half (n = 10) of SS and HS groups were engaged in an ET program (8 wks/5 d/wk/60 min/day). At this time, a blood sample was collected for biochemical analysis. At the end of protocol (17-weeks) anatomic measures were assessed. Heart, liver, femur and visceral fat were weighted and blood was collected again. Liver section was used for histopathological examination. RESULTS: At 17-weeks, high-fat diet increased visceral adiposity (HS vs. SS), which was counteracted by both exercises. However, ET was the only intervention able to diminished obesity-related measures and the histological features of NASH. Moreover, blood analysis at 9 weeks showed that high-fat diet increased ALT, AST, cholesterol and HDL while VLDL and TG levels were decreased (HS vs. SS). Notably, although these parameters were counteracted after 9-weeks of VPA, they were transitory and not observed after 17-weeks. CONCLUSIONS: ET used as a therapeutic tool mitigated the clinical/anatomical-related features induced by Liber-DeCarli diet, thus possibly contributing to control obesity and metabolic disorders.
Asunto(s)
Dieta Alta en Grasa/efectos adversos , Terapia por Ejercicio/métodos , Grasa Intraabdominal/patología , Hígado/fisiopatología , Actividad Motora , Animales , Modelos Animales de Enfermedad , Masculino , Enfermedad del Hígado Graso no Alcohólico/inducido químicamente , Enfermedad del Hígado Graso no Alcohólico/patología , Enfermedad del Hígado Graso no Alcohólico/fisiopatología , Ratas , Ratas Sprague-Dawley , Resultado del TratamientoRESUMEN
Mitochondrial membrane lipid composition is a critical factor in non-alcoholic steatohepatitis (NASH). Exercise is the most prescribed therapeutic strategy against NASH and a potential modulator of lipid membrane. Thus, we aimed to analyze whether physical exercise exerted preventive (voluntary physical activity - VPA) and therapeutic (endurance training - ET) effect on NASH-induced mitochondrial membrane changes. Sprague-Dawley rats (n=36) were divided into standard-diet sedentary (SS, n=12), standard-diet VPA (SVPA, n=6), high-fat diet sedentary (HS, n=12) and high-fat diet VPA (HVPA, n=6). After 9 weeks of diet-specific feeding, half of SS and HS group were engaged in an ET program for 8 weeks/5 day/week/1h/day (SET, HET). Liver mitochondria were isolated for oxygen consumption and transmembrane-electric potential (ΔΨ) assays. Mitochondrial phospholipid classes and fatty acids were quantified through thin layer chromatography and gas chromatography, respectively, while cardiolipin (CL), phosphatidylcholine (PC) phosphatidylethanolamine (PE) and phosphatidylinositol (PI) molecular profile was determined by electrospray mass spectrometry. In parallel with histological signs of NASH, high-fat diet decreased PI, CL and PC/PE ratio, whereas PE and phosphatidic acid content increased in sedentary animals (HS vs. SS). Moreover, a decrease in linolelaidic, monounsaturated fatty acids content and an increase in saturated fatty acids (SFAS) were observed. Along with phospholipidomic alterations, HS animals showed a decrease in respiratory control ratio (RCR), ΔΨ and FCCP-induced uncoupling respiration (HS vs. SS). Both phospholipidomic (PC/PE, SFAS) and mitochondrial respiratory alterations were counteracted by exercise interventions. Exercise used as preventive (VPA) or therapeutic (ET) strategies preserved liver mitochondrial phospholipidomic profile and maintained mitochondrial function in a model of NASH.
Asunto(s)
Ácidos Grasos/metabolismo , Lípidos de la Membrana/metabolismo , Mitocondrias Hepáticas/patología , Membranas Mitocondriales/patología , Enfermedad del Hígado Graso no Alcohólico/patología , Fosfolípidos/metabolismo , Condicionamiento Físico Animal/fisiología , Animales , Células Cultivadas , Masculino , Mitocondrias Hepáticas/metabolismo , Membranas Mitocondriales/metabolismo , Enfermedad del Hígado Graso no Alcohólico/metabolismo , Consumo de Oxígeno , Ratas , Ratas Sprague-DawleyRESUMEN
Exercise is considered a non-pharmacological tool against several lifestyle disorders in which mitochondrial dysfunction is involved. The present study aimed to analyze the preventive (voluntary physical activity-VPA) and therapeutic (endurance training-ET) role of exercise against non-alcoholic steatohepatitis (NASH)-induced liver mitochondrial dysfunction. Sixty male Sprague-Dawley rats were divided into standard-diet sedentary (SS, n=20), standard-diet VPA (SVPA, n=10), high-fat diet sedentary (HS, n=20) and high-fat diet VPA (HVPA, n=10). After 9weeks of diet-treatment, half of SS and HS animals were engaged in an ET program (SET and HET) for 8weeks, 5days/week and 60min/day. Liver mitochondrial oxygen consumption and transmembrane-electric potential (ΔΨ) were evaluated in the presence of glutamate-malate (G/M), palmitoyl-malate (P/M) and succinate (S/R). Mitochondrial enzymes activity, lipid and protein oxidation, oxidative phosphorylation (OXPHOS) subunits, cytochrome c, adenine nucleotide translocator (ANT) and uncoupling protein-2 (UCP2) content were assessed. HS groups show the histological features of NASH in parallel with decreased ΔΨ and respiratory control (RCR) and ADP/O ratios (G/M and P/M). A state 3 decrease (G/M and S/R), FCCP-induced uncoupling respiration (S/R) and ANT content were also observed. Both exercise types counteracted oxygen consumption (RCR, ADP/O and FCCP-uncoupling state) impairments and improved ΔΨ (lag-phase). In conclusion, exercise prevented or reverted (VPA and ET, respectively) the bioenergetic impairment induced by NASH, but only ET positively remodeled NASH-induced liver structural damage and abnormal mitochondria. It is possible that alterations in inner membrane integrity and fatty acid oxidation may be related to the observed phenotypes induced by exercise.
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Metabolismo Energético , Hígado Graso Alcohólico/fisiopatología , Hígado/patología , Hígado/fisiopatología , Mitocondrias/patología , Mitocondrias/fisiología , Condicionamiento Físico Animal , Animales , Modelos Animales de Enfermedad , Hígado Graso Alcohólico/terapia , Mitocondrias/ultraestructura , Ratas Sprague-DawleyRESUMEN
Nonalcoholic fatty liver disease, encompassing hepatic steatosis, nonalcoholic steatohepatitis (NASH), fibrosis and cirrhosis, is a significant health problem associated with modern lifestyle, based on caloric overconsumption and physical inactivity. Although the mechanisms associated with progression from the 'benign' steatosis to NASH are still elusive, mitochondrial dysfunction seems to play an important role in this degenerative process. Degeneration of mitochondrial function during NASH has been associated with impaired ß-oxidation, oxidative phosphorylation and increased reactive oxygen species production, contributing to hepatocyte death and inflammatory response. Despite the fact that several therapeutic approaches can be used in the context of NASH, including insulin-sensitizing agents, anti-obesity drugs, lipid-lowering drugs or mitochondrial-targeted drugs, dietary and physical activity are still the most effective strategies. In fact, active lifestyles decrease insulin resistance and body weight and result in decreased histological signs of liver injury. In fatty liver, physical activity prevents the disease progression through mitochondrial adaptations, namely by increasing cytochrome c content, enzyme activities and fatty acid oxidation, which are lost after some days of physical inactivity. However, less is known about the effect of physical activity on NASH-associated mitochondrial dysfunction. After a brief characterization of NASH and its association with liver mitochondrial (dys)function, the present review addresses the impact of physical (in)activity on NASH and, particularly, the possible contribution of active lifestyles to the modulation of liver mitochondrial dysfunction.
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Terapia por Ejercicio , Enfermedades Mitocondriales/prevención & control , Mitofagia/fisiología , Enfermedad del Hígado Graso no Alcohólico/complicaciones , Humanos , Mitocondrias Hepáticas/fisiología , Enfermedades Mitocondriales/fisiopatología , Enfermedad del Hígado Graso no Alcohólico/fisiopatología , Conducta SedentariaRESUMEN
Liver steatosis (non-alcoholic fatty liver disease, NAFLD) is deemed as the hepatic face of the metabolic syndrome, with both physical inactivity and hypercaloric/unbalanced diet, together with increasing age playing a role as predisposing factors. Consequently, one of the most effective strategies used to counteract this scenario is physical exercise. Given the importance of redox signaling in cellular remodeling, in which mitochondria are closely implicated along with important roles on substrate oxidation, here we briefly review the effects of both acute and chronic forms of physical exercise on the modulation of hepatic redox state, highlighting the relevance of mitochondrial metabolism and function in the induction of liver phenotypes that antagonize metabolic alterations associated with liver metabolic diseases.
Asunto(s)
Ejercicio Físico , Hepatopatías/terapia , Mitocondrias Hepáticas/metabolismo , Humanos , Hepatopatías/metabolismo , Oxidación-Reducción , Estrés OxidativoRESUMEN
The use of DOX (doxorubicin), an antibiotic used in oncological treatments, is limited by a dose-related cardiotoxicity against which acute exercise is protective. However, the mitochondrial-related mechanisms of this protection remain unknown. Therefore the present study aimed to determine the effects of an acute endurance exercise bout performed 24 h before DOX treatment on heart and liver mitochondrial function. A total of 20 adult male Wistar rats were divided into groups as follows: non-exercised with saline (NE + SAL), non-exercised DOX-treated (NE + DOX), exercised with saline (EX + SAL) and exercised DOX-treated (EX + DOX). The animals performed a 60 min exercise bout on a treadmill or remained sedentary 24 h before receiving either a DOX bolus (20 mg/kg of body weight) or saline. Heart and liver mitochondrial function [oxygen consumption, membrane potential (DeltaPsi) and cyclosporin-A-sensitive calcium-induced MPTP (mitochondrial permeability transition pore) opening] were evaluated. The activities of the respiratory complex, Mn-SOD (superoxide dismutase), caspases 3 and 9, as well as the levels of ANT (adenine nucleotide translocase), VDAC (voltage-dependent anion channel), CypD (cyclophilin D), Bax and Bcl-2, were measured. Acute exercise prevented the decreased cardiac mitochondrial function (state 3, phosphorylative lagphase; maximal DeltaPsi generated both with complex I- and II-linked substrates and calcium-induced MPTP opening) induced by DOX treatment. Exercise also prevented the DOX-induced decreased activity of cardiac mitochondrial chain complexes I and V, and increased caspase 3 and 9 activities. DOX administration and exercise caused increased cardiac mitochondrial SOD activity. Exercise ameliorated liver mitochondrial complex activities. No alterations were observed in the measured MPTP and apoptosis-related proteins in heart and liver mitochondria. The results demonstrate that acute exercise protects against cardiac mitochondrial dysfunction, preserving mitochondrial phosphorylation capacity and attenuating DOX-induced decreased tolerance to MPTP opening.