RESUMEN
Non-alcoholic fatty liver disease (NAFLD) is projected to be the most common chronic liver disease worldwide and is closely linked to obesity, insulin resistance and type 2 diabetes. Currently, no pharmacological treatments are available to treat NAFLD, and lifestyle modification, including dietary interventions, is the only remedy. Therefore, we conducted a study to determine whether supplementation with medium-chain triglycerides (MCTs), containing a mixture of C8 and C10 (60/40), attenuates NAFLD in obese and insulin-resistant mice. To achieve that, we fed C57BL/6 male mice a high-fat diet (HFD) for 12 weeks to induce obesity and hepatic steatosis, after which obese mice were assigned randomly either to remain on the HFD or to transition to an HFD supplemented with MCTs (HFD + MCTs) or a low-fat diet (LFD) for 6 weeks as another dietary intervention model. Another group of mice was kept on an LFD throughout the study and used as a lean control group. Obese mice that transitioned to HFD + MCTs exhibited improvement in glucose and insulin tolerance tests, and the latter improvement was independent of changes in adiposity when compared with HFD-fed mice. Additionally, supplementation with MCTs significantly reduced hepatic steatosis, improved liver enzymes and decreased hepatic expression of inflammation-related genes to levels similar to those observed in obese mice transitioned to an LFD. Importantly, HFD + MCTs markedly lowered hepatic ceramide and diacylglycerol content and prevented protein kinase C-ε translocation to the plasma membrane. Our study demonstrated that supplementation with MCTs formulated mainly from C8 and C10 effectively ameliorated NAFLD in obese mice.
Asunto(s)
Diabetes Mellitus Tipo 2 , Resistencia a la Insulina , Insulinas , Enfermedad del Hígado Graso no Alcohólico , Masculino , Animales , Ratones , Ratones Endogámicos C57BL , Enfermedad del Hígado Graso no Alcohólico/tratamiento farmacológico , Dieta Alta en Grasa , Diglicéridos , Ratones Obesos , Suplementos Dietéticos , Obesidad , Ceramidas , Hígado , TriglicéridosRESUMEN
Skeletal muscle substrate preference for fuel is largely influenced by dietary macronutrient availability. The abundance of dietary carbohydrates promotes the utilization of glucose as a substrate for energy production, whereas an abundant dietary fat supply elevates rates of fatty acid (FA) oxidation. The objective of this study was to determine whether an obesogenic, high-fat, sucrose-enriched (HFS) diet or a carbohydrate-free ketogenic diet (KD) exert distinct effects on fat, glucose, and ketone metabolism in oxidative and glycolytic skeletal muscles. Male Wistar rats were fed either a HFS diet or a KD for 16 weeks. Subsequently, the soleus (Sol), extensor digitorum longus (EDL), and epitrochlearis (Epit) muscles were extracted to measure palmitate oxidation, insulin-stimulated glucose metabolism, and markers of mitochondrial biogenesis, ketolytic capacity, and cataplerotic and anaplerotic machinery. Sol, EDL, and Epit muscles from KD-fed rats preserved their ability to elevate glycogen synthesis and lactate production in response to insulin, whereas all muscles from rats fed with the HFS diet displayed blunted responses to insulin. The maintenance of metabolic flexibility with the KD was accompanied by muscle-fiber-type-specific adaptive responses. This was characterized by the Sol muscle in KD-fed rats enhancing mitochondrial biogenesis and ketolytic capacity without elevating its rates of FA oxidation in comparison with that in HFS feeding. Conversely, in the Epit muscle, rates of FA oxidation were increased, whereas the ketolytic capacity was markedly reduced by the KD in comparison with that by HFS feeding. In the EDL muscle, the KD also increased rates of FA oxidation, although it did so without altering its ketolytic capacity when compared to HFS feeding. In conclusion, even though obesogenic and ketogenic diets have elevated contents of fat and alter whole-body substrate partitioning, these two dietary interventions are associated with opposite outcomes with respect to skeletal muscle metabolic flexibility.
Asunto(s)
Dieta Alta en Grasa , Sacarosa , Masculino , Ratas , Animales , Dieta Alta en Grasa/efectos adversos , Ratas Wistar , Músculo Esquelético , Glucosa , Insulina , Estrés OxidativoRESUMEN
The purpose of this study was to determine whether the weight-reducing and fat burning effects of the ketogenic diet (KD) could be attributed to alterations in the energy dissipating pathways of brown adipose tissue (BAT) uncoupled oxidation, and white adipose tissue (WAT) browning and triacylglycerol (TAG) recycling. To investigate this, male Wistar rats were fed one of the following three diets for either 8 or 16 weeks: a standard chow (SC), a high-fat, sucrose-enriched (HFS) obesogenic diet, or a KD. At the end of the intervention, subcutaneous inguinal (Sc Ing) and epididymal (Epid) fat, and interscapular and aortic BAT (iBAT and aBAT, respectively) were extracted. These tissues were used for the analysis of proteins involved in WAT browning and thermogenesis. Isolated adipocytes from WAT were assayed for basal and isoproterenol (Iso)-stimulated lipolysis and basal and insulin-stimulated lipogenesis, and BAT adipocytes were assayed for the determination of coupled and uncoupled glucose and palmitate oxidation. Adiposity similarly increased in HFS- and KD-fed rats at weeks 8 and 16. However, in HFS-fed animals insulin-stimulated lipogenesis and Iso-stimulated lipolysis were impaired in WAT adipocytes, whereas in KD-fed animals these pathways remained intact. The KD also significantly elevated WAT glycerol kinase levels, and favored TAG recycling under conditions of enhanced lipolysis. In BAT, the KD significantly increased uncoupling protein-1 levels and uncoupled fat oxidation. In summary, the KD preserved insulin sensitivity and lipolytic capacity in WAT and also upregulated energy-dissipating pathways in BAT, but it was not sufficient to prevent an increase in adiposity.
Asunto(s)
Tejido Adiposo Pardo , Dieta Cetogénica , Ratas , Masculino , Animales , Tejido Adiposo Pardo/metabolismo , Adiposidad , Triglicéridos/metabolismo , Ratas Wistar , Obesidad/metabolismo , Tejido Adiposo Blanco/metabolismo , Insulina/metabolismo , Termogénesis , Tejido Adiposo/metabolismo , Dieta Alta en Grasa/efectos adversosRESUMEN
This study investigated the role of diacylglycerol (DAG)-mediated protein kinase C (PKC) activation, ceramide accumulation and inflammation in insulin-resistant female oxidative and glycolytic skeletal muscles induced by an obesogenic high-fat sucrose-enriched (HFS) diet. The HFS diet impaired insulin-stimulated AKTThr308 phosphorylation and glycogen synthesis, whereas rates of fatty acid oxidation and basal lactate production were significantly elevated in soleus (Sol), extensor digitorum longus (EDL) and epitrochlearis (Epit) muscles. Insulin resistance was accompanied by increases in triacylglycerol (TAG) and DAG contents in Sol and EDL, whereas in Epit muscles only TAG content and markers of inflammation were associated with HFS diet-induced insulin resistance. Analysis of membrane-bound/cytoplasmic PKC fractions revealed that the HFS diet promoted activation/translocation of PKCδ and θ isoforms in Sol, EDL and Epit muscles. However, none of these muscles displayed alterations in ceramide content in response to HFS feeding. This could be explained by a significant increase in Dgat2 mRNA expression in Sol, EDL and Epit muscles, which likely diverted most of the intramyocellular acyl-CoAs toward TAG synthesis instead of ceramides. Overall, this study helps elucidate the molecular mechanisms underlying insulin resistance caused by diet-induced obesity in female skeletal muscles with distinct fibre type compositions. KEY POINTS: Feeding female Wistar rats a high-fat sucrose-enriched diet (HFS) led to diacylglycerol (DAG)-induced PKC activation and insulin resistance in oxidative and glycolytic skeletal muscles. HFS diet-induced toll-like receptor 4 (Tlr4) expression did not lead to increased ceramide content in female skeletal muscles. In highly glycolytic female muscles, elevated TAG content and markers of inflammation underlay HFS diet-induced insulin resistance. The HFS diet suppressed glucose oxidation and increased lactate production in oxidative and glycolytic female muscles. Increased Dgat2 mRNA expression likely diverted most of the intramyocellular acyl-CoAs toward TAG synthesis and prevented ceramide formation in skeletal muscles of HFS-fed female rats.
Asunto(s)
Resistencia a la Insulina , Insulina , Ratas , Femenino , Animales , Insulina/metabolismo , Resistencia a la Insulina/fisiología , Ratas Wistar , Ceramidas/metabolismo , Diglicéridos/metabolismo , Músculo Esquelético/metabolismo , Triglicéridos/metabolismo , Dieta Alta en Grasa/efectos adversos , Proteína Quinasa C/metabolismo , ARN Mensajero/metabolismo , Inflamación/metabolismo , LactatosRESUMEN
Brown adipose tissue (BAT) is rich in mitochondria containing uncoupling protein 1 (UCP1), and dissipates energy through thermogenesis. However, even though BAT mass and its UCP1 content increase in rodents chronically fed a high-fat sucrose-enriched (HFS) diet, marked expansion of adiposity still occurs in these animals, suggesting insufficient BAT-mediated HFS diet-induced thermogenesis. Thus, the objective of this study was to investigate the metabolic and molecular mechanisms that regulate BAT thermogenesis in HFS-induced obesity. To accomplish this, rats were fed either a standard chow or HFS diet for 8 weeks. Subsequently, glucose and fatty acid metabolism and the molecular mechanisms underlying these processes were assessed in freshly isolated primary BAT adipocytes. Despite increasing BAT mass and its UCP1 content, the HFS diet reduced uncoupled glucose and palmitate oxidation in BAT adipocytes. It also markedly diminished tyrosine hydroxylase content and lipolysis in these cells. Conversely, glucose uptake, lactate production, glycerol incorporation into lipids, palmitate incorporation into triacylglycerol (TAG), phosphoenolpyruvate carboxykinase and glycerol kinase levels, and lipoprotein lipase and cluster of differentiation 36 gene expression were increased. In summary, a HFS diet enhanced glyceroneogenesis and shifted BAT metabolism toward TAG synthesis by impairing UCP1-mediated substrate oxidation and by enhancing fatty acid esterification in intact brown adipocytes. These adaptive metabolic responses to chronic HFS feeding attenuated BAT thermogenic capacity and favoured the development of obesity. KEY POINTS: Despite increasing brown adipose tissue (BAT) mass and levels of thermogenic proteins such as peroxisome proliferator-activated receptor γ coactivator 1α, carnitine palmitoyltransferase 1B and uncoupling protein 1 (UCP1), an obesogenic high-fat sucrose-enriched (HFS) diet attenuated uncoupled glucose and fatty acid oxidation in brown adipocytes. Brown adipocytes diverted glycerol and fatty acids toward triacylglycerol (TAG) synthesis by elevating the cellular machinery that promotes fatty acid uptake along with phosphoenolpyruvate carboxykinase and glycerol kinase levels. The HFS diet increased glucose uptake that supported lactate production and provided substrate for glyceroneogenesis and TAG synthesis in brown adipocytes. Impaired UCP-1-mediated thermogenic capacity and enhanced TAG storage in BAT adipocytes were consistent with reduced adipose triglyceride lipase and tyrosine hydroxylase levels in HFS diet-fed animals.
Asunto(s)
Tejido Adiposo Pardo , Glicerol , Ratas , Animales , Tejido Adiposo Pardo/metabolismo , Proteína Desacopladora 1/genética , Glicerol/metabolismo , Glicerol Quinasa/metabolismo , Fosfoenolpiruvato/metabolismo , Tirosina 3-Monooxigenasa/metabolismo , Proteínas Mitocondriales/genética , Proteínas Mitocondriales/metabolismo , Dieta , Obesidad/etiología , Obesidad/metabolismo , Triglicéridos/metabolismo , Adipocitos Marrones/metabolismo , Glucosa/metabolismo , Ácidos Grasos/metabolismo , Termogénesis/fisiologíaRESUMEN
OBJECTIVE: The ketogenic diet (KD) has been reported to reverse metabolic dysfunction in obesity. However, it remains unknown how the KD affects the balance between the classical and counterregulatory renin-angiotensin system (RAS) arms in adipose tissue, which carries important implications for metabolic function in adipocytes. The aim of this study was to compare the effects of the obesogenic diet and the KD on RAS balance in white and brown fat. METHODS: Nine male Wistar rats were fed a standard chow (SC), 11 fed a high-fat sucrose-enriched (HFS) obesogenic diet, and 12 a KD. At the end of the 8-wk feeding period, subcutaneous inguinal (Sc Ing), epididymal (Epid), and interscapular brown adipose tissue (iBAT) fat depots were extracted and subsequently used for the measurement of RAS proteins and MasR gene expression. RESULTS: In SC-fed rats, the Sc Ing fat displayed the highest levels of angiotensin-converting enzyme (ACE)1, but very low levels of angiotensin II types 1 and 2 receptors (AT1R and AT2R) and ACE2. Conversely, the highest levels of ACE2, AT1R, and AT2R were found in iBAT. The HFS diet increased AT1R protein in Sc Ing fat and iBAT, whereas the KD maintained low AT1R levels in these fat depots. However, in Sc Ing and Epid fat depots, the KD elevated AT2R levels and significantly reduced Epid ACE1 levels. CONCLUSION: Despite fat depot-specific differences in RAS components, the obesogenic diet promoted the classical RAS arm, whereas the KD attenuated it and enhanced the counterregulatory arm.
Asunto(s)
Tejido Adiposo Pardo , Tejido Adiposo Blanco , Dieta Cetogénica , Sistema Renina-Angiotensina , Animales , Masculino , Ratas , Tejido Adiposo Pardo/metabolismo , Enzima Convertidora de Angiotensina 2 , Ratas Wistar , Tejido Adiposo Blanco/metabolismoRESUMEN
Obesity-associated insulin resistance plays a major role in the pathogenesis of non-alcoholic fatty liver disease (NAFLD). The accumulation of diacylglycerol (DAG), ceramides and inflammation are key factors that cause NAFLD. In recent years, the ketogenic diet (KD) has emerged as an effective non-pharmacological intervention for the treatment of NAFLD and other obesity-related metabolic disorders. What remains undetermined is how the KD affects DAG and ceramide content and insulin sensitivity in the liver. Thus, this research was designed to assess these variables, as well as glucose and fat metabolism and markers of inflammation in livers of rats exposed for 8 weeks to one of the following diets: standard chow (SC), obesogenic high-fat, sucrose-enriched diet (HFS) or a KD. Despite having a higher fat content than the HFS diet, the KD did not cause steatosis and preserved hepatic insulin signalling. The KD reduced DAG content and protein kinase C-ε activity, but markedly increased liver ceramide content. However, whereas the KD increased ceramide synthase 2 (CerS2) expression, it suppressed CerS6 expression, an effect that promoted the production of beneficial very long-chain ceramides instead of harmful long-chain ceramides. The KD also enhanced the liver expression of key genes involved in mitochondrial biogenesis and fatty acid oxidation (Pgc-1α and Fgf21), suppressed inflammatory genes (Tnfα, Nf-kb, Tlr4 and Il6), and shifted substrate away from de novo lipogenesis. Thus, through multiple mechanisms the KD exerted anti-steatogenic and insulin-sensitizing effects in the liver, which supports the use of this dietary intervention to treat NAFLD. KEY POINTS: The accumulation of diacylglycerol (DAG), ceramides and inflammation are key factors that cause insulin resistance and non-alcoholic fatty liver disease (NAFLD). This study provides evidence that a ketogenic diet (KD) rich in fat and devoid of carbohydrate reduced DAG content and preserved insulin signalling in the liver. The KD shifted metabolism away from lipogenesis by enhancing genes involved in mitochondrial biogenesis and fatty acid oxidations in the liver. The KD also promoted the production of beneficial very long-chain ceramides instead of potentially harmful long-chain ceramides. Through multiple mechanisms, the KD exerted anti-steatogenic and insulin-sensitizing effects in the liver, which supports the use of this dietary intervention to treat NAFLD.
Asunto(s)
Dieta Cetogénica , Resistencia a la Insulina , Enfermedad del Hígado Graso no Alcohólico , Animales , Ceramidas/metabolismo , Dieta Alta en Grasa/efectos adversos , Diglicéridos/farmacología , Ácidos Grasos/metabolismo , Inflamación/metabolismo , Insulina/metabolismo , Resistencia a la Insulina/fisiología , Lipogénesis , Hígado/metabolismo , Masculino , Enfermedad del Hígado Graso no Alcohólico/metabolismo , Obesidad/metabolismo , Proteína Quinasa C/metabolismo , RatasRESUMEN
This study investigates whether ladder climbing (LC), as a model of resistance exercise, can reverse whole-body and skeletal muscle deleterious metabolic and inflammatory effects of high-fat (HF) diet-induced obesity in mice. To accomplish this, Swiss mice were fed for 17 weeks either standard chow (SC) or an HF diet and then randomly assigned to remain sedentary or to undergo 8 weeks of LC training with progressive increases in resistance weight. Prior to beginning the exercise intervention, HF-fed animals displayed a 47% increase in body weight (BW) and impaired ability to clear blood glucose during an insulin tolerance test (ITT) when compared to SC animals. However, 8 weeks of LC significantly reduced BW, adipocyte size, as well as glycemia under fasting and during the ITT in HF-fed rats. LC also increased the phosphorylation of AktSer473 and AMPKThr172 and reduced tumor necrosis factor-alpha (TNF-α) and interleukin 1 beta (IL1-ß) contents in the quadriceps muscles of HF-fed mice. Additionally, LC reduced the gene expression of inflammatory markers and attenuated HF-diet-induced NADPH oxidase subunit gp91phox in skeletal muscles. LC training was effective in reducing adiposity and the content of inflammatory mediators in skeletal muscle and improved whole-body glycemic control in mice fed an HF diet.
Asunto(s)
Resistencia a la Insulina , Entrenamiento de Fuerza , Tejido Adiposo/metabolismo , Animales , Glucemia/metabolismo , Dieta Alta en Grasa/efectos adversos , Humanos , Resistencia a la Insulina/fisiología , Ratones , Ratones Endogámicos C57BL , Músculo Esquelético/metabolismo , Obesidad/metabolismo , Obesidad/terapia , RatasRESUMEN
BACKGROUND: Obesity increases the severity of SARS-CoV-2 outcomes. Thus, this study tested whether obesogenic and ketogenic diets distinctly affect SARS-CoV-2 entry proteins and the renin-angiotensin system (RAS) in rat pulmonary and cardiac tissues. METHODS: Male Sprague-Dawley rats were fed either standard chow (SC), a high-fat sucrose-enriched diet (HFS), or a ketogenic diet (KD) for 16 weeks. Afterwards, levels of angiotensin converting enzyme 2 (ACE2), transmembrane protease serine 2 (TMPRSS2), RAS components, and inflammatory genes were measured in the lungs and hearts of these animals. RESULTS: In the lungs, HFS elevated ACE2 and TMPRSS2 levels relative to SC diet, whereas the KD lowered the levels of these proteins and the gene expressions of toll-like receptor 4 and interleukin-6 receptor relative to HFS. The diets did not alter ACE2 and TMPRSS2 in the heart, although ACE2 was more abundant in heart than lung tissues. CONCLUSION: Diet-induced obesity increased the levels of viral entry proteins in the lungs, providing a mechanism whereby SARS-CoV-2 infectivity can be enhanced in obese individuals. Conversely, by maintaining low levels of ACE2 and TMPRSS2 and by exerting an anti-inflammatory effect, the KD can potentially attenuate the severity of infection and migration of SARS-CoV-2 to other ACE2-expressing tissues.
Asunto(s)
Enzima Convertidora de Angiotensina 2/metabolismo , COVID-19/patología , Dieta Alta en Grasa/efectos adversos , Dieta Cetogénica/métodos , Pulmón/metabolismo , Miocardio/metabolismo , Serina Endopeptidasas/metabolismo , Enzima Convertidora de Angiotensina 2/genética , Animales , Biomarcadores/metabolismo , COVID-19/complicaciones , COVID-19/metabolismo , Modelos Animales de Enfermedad , Masculino , Obesidad/complicaciones , Obesidad/metabolismo , Ratas , Ratas Sprague-Dawley , Sistema Renina-Angiotensina , SARS-CoV-2 , Serina Endopeptidasas/genética , Internalización del VirusRESUMEN
This study investigated whether oxidative and glycolytic rat skeletal muscles respond differently to a high-fat (HF) sucrose-enriched diet with respect to diacylglycerol (DAG) and ceramides accumulation, protein kinase C (PKC) activation, glucose metabolism, and the expression of inflammatory genes. HF diet (8 weeks) suppressed insulin-stimulated glycogen synthesis and glucose oxidation in soleus (Sol), extensor digitorum longus (EDL) and epitrochlearis (Epit) muscles. However, DAG and ceramides levels increased in Sol and EDL, but not in Epit muscles of HF-fed rats. Additionally, membrane-bound PKC-delta and PKC-theta increased in Sol and EDL, whereas in Epit muscles both PKC isoforms were reduced by HF diet. In Epit muscles, HF diet also increased the expression of tumor necrosis factor-α (TNF-α) receptors (CD40 and FAS), toll-like receptor 4 (TLR4), and nuclear factor kappa light polypeptide gene enhancer in B cells (NF-kB), whereas in Sol and EDL muscles the expression of these inflammatory genes remained unchanged upon HF feeding. In conclusion, HF diet caused DAG and ceramides accumulation, PKC activation, and the induction of inflammatory pathways in a fiber type-specific manner. These findings help explain why oxidative and glycolytic muscles similarly develop insulin resistance, despite major differences in their metabolic characteristics and responsiveness to dietary lipid abundance.
Asunto(s)
Glucólisis/inmunología , Resistencia a la Insulina/inmunología , Músculo Esquelético/metabolismo , Obesidad/metabolismo , Animales , Ceramidas/análisis , Ceramidas/metabolismo , Dieta Alta en Grasa/efectos adversos , Sacarosa en la Dieta/efectos adversos , Diglicéridos/análisis , Diglicéridos/metabolismo , Modelos Animales de Enfermedad , Humanos , Inflamación/diagnóstico , Inflamación/inmunología , Inflamación/metabolismo , Insulina/metabolismo , Masculino , Músculo Esquelético/inmunología , Obesidad/etiología , Obesidad/inmunología , Estrés Oxidativo/inmunología , RatasRESUMEN
Increased myocardial autophagy has been established as an important stress-induced cardioprotective response. Three weeks after generating cardiomyocyte-specific autophagy deficiency, via inducible deletion of autophagy-related protein 7 (Atg7), we found that these mice (AKO) had increased body weight and fat mass without altered food intake. Glucose and insulin tolerance tests indicated reduced insulin sensitivity in AKO mice. Metabolic cage analysis showed reduced ambulatory activity and oxygen consumption with a trend of elevated respiratory exchange ratio in AKO mice. Direct analysis of metabolism in subcutaneous and visceral adipocytes showed increased glucose oxidation and reduced ATGL expression and HSL phosphorylation with no change in lipid synthesis or fatty acid oxidation. Importantly, we found AKO mice had reduced myocardial and circulating levels of atrial natriuretic peptide (ANP), an established mediator of myocardial-adipose cross talk. When normal ANP levels were restored to AKO mice with use of osmotic pump, the metabolic dysfunction evident in AKO mice was corrected. We conclude that cardiac autophagy deficiency alters myocardial-adipose cross talk via decreased ANP levels with adverse metabolic consequences.
Asunto(s)
Tejido Adiposo/metabolismo , Factor Natriurético Atrial/metabolismo , Proteína 7 Relacionada con la Autofagia/genética , Autofagia/fisiología , Miocardio/metabolismo , Adipocitos/metabolismo , Animales , Proteína 7 Relacionada con la Autofagia/metabolismo , Glucosa/metabolismo , Insulina/metabolismo , Resistencia a la Insulina/fisiología , Ratones , Ratones Noqueados , Palmitatos/metabolismo , FosforilaciónRESUMEN
This study investigated whether regulation of the renin-angiotensin system (RAS) by enalapril and/or aerobic exercise training (AET) causes browning of the subcutaneous white adipose tissue (sWAT). C57BL/6 mice were fed either a standard chow or a high-fat (HF) diet for 16 weeks. At Week 8, HF-fed animals were divided into sedentary (HF), enalapril (HF-E), AET (HF-T), and enalapril plus AET (HF-ET) groups. Subsequently, sWAT was extracted for morphometry, determination of RAS expression, and biomarkers of WAT browning. The HF group displayed adipocyte hypertrophy and induction of the classical RAS axis. Conversely, all interventions reduced adiposity and induced the counterregulatory RAS axis. However, only AET raised plasma irisin, increased peroxisome proliferator-activated receptor-γ coactivator-1α, and uncoupling protein-1 levels, and the expression of PR-domain containing 16 in sWAT. Therefore, we concluded that AET-induced sWAT browning was independent of the counterregulatory axis shifting of RAS in HF diet-induced obesity.
Asunto(s)
Tejido Adiposo Pardo/efectos de los fármacos , Tejido Adiposo Pardo/fisiopatología , Adiposidad/efectos de los fármacos , Enalapril/farmacología , Condicionamiento Físico Animal/fisiología , Carrera/fisiología , Grasa Subcutánea/efectos de los fármacos , Tejido Adiposo Pardo/metabolismo , Tejido Adiposo Blanco/metabolismo , Tejido Adiposo Blanco/fisiopatología , Animales , Biomarcadores/metabolismo , Dieta Alta en Grasa/efectos adversos , Masculino , Ratones , Ratones Endogámicos C57BL , Obesidad/metabolismo , Obesidad/fisiopatología , Sistema Renina-Angiotensina/efectos de los fármacos , Grasa Subcutánea/metabolismo , Grasa Subcutánea/fisiopatologíaRESUMEN
The objective of this study was to investigate whether the n-3 polyunsaturated fatty acids (PUFAs) docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) can directly regulate glucose and fat metabolism in skeletal muscle besides exerting anti-inflammatory effects. To accomplish this, L6 skeletal muscle cells were treated with 50 µM of either DHA or EPA for 1, 3, and 5 days. Here, we report that basal and insulin-stimulated rates of glucose uptake, glycogen synthesis, protein kinase B (AKT), and glycogen synthase kinase 3 (GSK3) phosphorylation were not affected by DHA or EPA. However, glucose and palmitate oxidation were consistently elevated by DHA treatment, whereas EPA only increased this variable transiently. Similarly, only DHA caused significant and sustained increases in AMP-activated protein kinase (AMPK) phosphorylation and protein levels of carnitine-palmitoyl transferase-1b (CPT1b) and peroxisome proliferator-activated receptor gamma coactivator-1α (PGC-1α) in skeletal muscle cells. DHA also caused a larger anti-inflammatory effect than EPA in these cells. In conclusion, besides exerting anti-inflammatory effects, DHA and EPA directly regulated glucose and fat metabolism in skeletal muscle cells, although DHA was more effective in doing so than EPA. Thus, by directly enhancing glucose and fat oxidation, DHA may increase glucose disposal and reduce intramyocellular lipid accumulation.
Asunto(s)
Ácidos Docosahexaenoicos/metabolismo , Ácido Eicosapentaenoico/metabolismo , Glucosa/metabolismo , Metabolismo de los Lípidos/fisiología , Células Musculares/metabolismo , Proteínas Quinasas Activadas por AMP/metabolismo , Animales , Antiinflamatorios/metabolismo , Carnitina O-Palmitoiltransferasa/metabolismo , Línea Celular , Músculo Esquelético/citología , Músculo Esquelético/metabolismo , Palmitatos/metabolismo , Coactivador 1-alfa del Receptor Activado por Proliferadores de Peroxisomas gamma/metabolismo , Fosforilación , RatasRESUMEN
Adiponectin regulates white adipose tissue (WAT) metabolism and promotes insulin-sensitizing and anti-atherosclerotic effects in vivo. In this context, small molecule adiponectin receptor agonists have become of great therapeutic value for the treatment of metabolic diseases. Here, we investigated the effects of the adiponectin mimetic compound ALY688 on WAT metabolism. To accomplish this, rat epididymal (Epid) and subcutaneous inguinal (Sc Ing) adipocytes were isolated and incubated with ALY688. Subsequently, several parameters of glucose and fat metabolism were assessed. ALY688 promoted AMP-activated protein kinase (AMPK) and acetyl-CoA carboxylase (ACC) phosphorylation, enhanced glucose oxidation, and suppressed fat oxidation in adipocytes from both fat depots. ALY688 did not affect basal and insulin-stimulated rates of glucose uptake, glucose incorporation into lipids, and AKTSer473 and p38 mitogen-activated protein kinase (MAPK) phosphorylations in either Epid or Sc Ing adipocytes. ALY688 did not alter basal lipolysis in Epid and Sc Ing adipocytes, but it enhanced isoproterenol-induced lipolysis in Epid adipocytes. Adiponectin receptor 2 (AdipoR2) mRNA was the prevalent isoform expressed in all adipocytes, and Epid adipocytes displayed significantly higher AdipoR2 mRNA expression than Sc Ing adipocytes. In conclusion, ALY688 can regulate adiposity and affect glycaemic control by altering substrate portioning in the WAT in a fat depot-specific manner.
Asunto(s)
Adipocitos/efectos de los fármacos , Adipocitos/metabolismo , Adiponectina/farmacología , Metabolismo Energético/efectos de los fármacos , Glucosa/metabolismo , Adiponectina/análogos & derivados , Animales , Grasa Intraabdominal/efectos de los fármacos , Grasa Intraabdominal/metabolismo , Metabolismo de los Lípidos/efectos de los fármacos , Lipogénesis/efectos de los fármacos , Lipólisis/efectos de los fármacos , Imitación Molecular , Oxidación-Reducción/efectos de los fármacos , Ratas , Grasa Subcutánea/efectos de los fármacos , Grasa Subcutánea/metabolismoRESUMEN
BACKGROUND: Obesity can be characterized by low-grade chronic inflammation and is associated with an excesso production of reactive oxygen species, factors that contribute to coronary heart disease and other cardiomyopathies. OBJECTIVE: To verify the effects of resistance exercise training on oxidative stress and inflammatory parameters on mice with obesity induced by a high-fat diet (HFD). METHODS: 24 Swiss mice were divided into 4 groups: standard diet (SD), SD + resistance exercise (SD + RE), diet-induced obesity (DIO), DIO + RE. The animals were fed SD or HFD for 26 weeks and performed resistance exercises in the last 8 weeks of the study. The insulin tolerance test (ITT) and body weight monitoring were performed to assess the clinical parameters. Oxidative stress and inflammation parameters were evaluated in the cardiac tissue. Data were expressed by mean and standard deviation (p < 0.05). RESULTS: The DIO group had a significant increase in reactive oxygen species levels and lipid peroxidation with reduction after exercise. Superoxide dismutase and the glutathione system showed no significant changes in DIO animals, with an increase in SD + RE. Only catalase activity decreased with both diet and exercise influence. There was an increase in tumor necrosis factor-alpha (TNF-α) in the DIO group, characterizing a possible inflammatory condition, with a decrease when exposed to resistance training (DIO+RE). CONCLUSION: The DIO resulted in a redox imbalance in cardiac tissue, but the RE was able to modulate these parameters, as well as to control the increase in TNF-α levels.
Asunto(s)
Dieta Alta en Grasa/efectos adversos , Peroxidación de Lípido/fisiología , Miocardio/química , Estrés Oxidativo/fisiología , Entrenamiento de Fuerza , Factor de Necrosis Tumoral alfa/análisis , Animales , Inflamación/fisiopatología , Resistencia a la Insulina , Masculino , Ratones , Condicionamiento Físico Animal , Factores de TiempoRESUMEN
Abstract Background: Obesity can be characterized by low-grade chronic inflammation and is associated with an excesso production of reactive oxygen species, factors that contribute to coronary heart disease and other cardiomyopathies. Objective: To verify the effects of resistance exercise training on oxidative stress and inflammatory parameters on mice with obesity induced by a high-fat diet (HFD). Methods: 24 Swiss mice were divided into 4 groups: standard diet (SD), SD + resistance exercise (SD + RE), diet-induced obesity (DIO), DIO + RE. The animals were fed SD or HFD for 26 weeks and performed resistance exercises in the last 8 weeks of the study. The insulin tolerance test (ITT) and body weight monitoring were performed to assess the clinical parameters. Oxidative stress and inflammation parameters were evaluated in the cardiac tissue. Data were expressed by mean and standard deviation (p < 0.05). Results: The DIO group had a significant increase in reactive oxygen species levels and lipid peroxidation with reduction after exercise. Superoxide dismutase and the glutathione system showed no significant changes in DIO animals, with an increase in SD + RE. Only catalase activity decreased with both diet and exercise influence. There was an increase in tumor necrosis factor-alpha (TNF-α) in the DIO group, characterizing a possible inflammatory condition, with a decrease when exposed to resistance training (DIO+RE). Conclusion: The DIO resulted in a redox imbalance in cardiac tissue, but the RE was able to modulate these parameters, as well as to control the increase in TNF-α levels.
Resumo Fundamento: A obesidade pode ser caracterizada por uma inflamação crônica de baixo grau e está associada à produção excessiva de espécies reativas de oxigênio, fatores que contribuem para doenças coronarianas e outras cardiomiopatias. Objetivo: Verificar os efeitos do treinamento resistido sobre os parâmetros de estresse oxidativo e parâmetro inflamatório em camundongos com obesidade induzida por dieta hiperlipídica (DIO). Métodos: 24 camundongos Swiss foram divididos em 4 grupos: dieta padrão (DP), DP + exercício resistido (DP+ER), obesidade induzida por DIO, DIO + ER. Os animais foram alimentados por 26 semanas com DP ou hiperlipídica realizando treinamento resistido nas 8 semanas finais do estudo. Para avaliar parâmetros clínicos foi realizado o teste de tolerância à insulina (TTI) e monitoramento do peso corporal. No tecido cardíaco foram avaliados parâmetros de estresse oxidativo e inflamação. Dados expressos por média e desvio padrão (p < 0,05). Resultados: O grupo DIO teve um aumento significativo nos níveis espécies reativas e peroxidação lipídica com redução após o exercício. A superóxido dismutase e o sistema glutationa não demonstraram alterações importantes nos animais DIO, com elevação perante DP+ER. Somente a atividade da catalase reduziu tanto com influência da dieta como do exercício. Ocorreu um aumento do fator de necrose tumoral-alfa (TNF-α) no grupo DIO, caracterizando um possível quadro inflamatório, com redução quando expostos ao treino resistido (DIO+ER). Conclusão: A DIO ocasionou um desequilíbrio redox no tecido cardíaco, porém o ER foi capaz de modular estes parâmetros, bem como controlar o aumento do TNF-α.
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Animales , Masculino , Ratas , Peroxidación de Lípido/fisiología , Factor de Necrosis Tumoral alfa/análisis , Estrés Oxidativo/fisiología , Entrenamiento de Fuerza , Dieta Alta en Grasa/efectos adversos , Miocardio/química , Condicionamiento Físico Animal , Factores de Tiempo , Resistencia a la Insulina , Inflamación/fisiopatologíaRESUMEN
The objective of this study was to investigate whether cold-induced browning of the subcutaneous (Sc) inguinal (Ing) white adipose tissue (WAT) increases the capacity of this tissue to oxidize fatty acids through uncoupling protein 1 (UCP1)-mediated thermogenesis. To accomplish that, rats were acclimated to cold (4°C for 7 days). Subsequently, interscapular and aortic brown adipose tissues (iBAT and aBAT, respectively), epididymal (Epid), and Sc Ing WAT were used for adipocyte isolation. In BAT adipocytes, cold acclimation increased UCP1 content and palmitate oxidation either in the absence or presence of oligomycin, whereas in Sc Ing adipocytes glucose and palmitate oxidation were not affected, although multilocular adipocytes were formed and UCP1 content increased upon cold acclimation in the WAT. Furthermore, isoproterenol-stimulated cold Sc Ing adipocytes exhibited significantly lower rates of palmitate oxidation than control cells when exposed to oligomycin. These findings provide evidence that, despite increasing UCP1 levels, cold acclimation essentially reduced mitochondrial uncoupling-mediated fat oxidation in Sc Ing adipocytes. Conversely, glycerol kinase and phosphoenolpyruvate carboxykinase levels, isoproterenol-induced lipolysis, as well as glycerol and palmitate incorporation into lipids significantly increased in these cells. Therefore, instead of UCP1-mediated mitochondrial uncoupling, cold acclimation increased the capacity of Sc Ing adipocytes to export fatty acids and enhanced key components of the triacylglycerol resynthesis pathway in the Sc Ing WAT.
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Lipólisis/fisiología , Mitocondrias/metabolismo , Proteínas Mitocondriales/metabolismo , Triglicéridos/metabolismo , Proteína Desacopladora 1/metabolismo , Aclimatación/fisiología , Tejido Adiposo Pardo/metabolismo , Tejido Adiposo Blanco/metabolismo , Animales , Frío , Metabolismo Energético/fisiología , Masculino , Oxidación-Reducción , Ratas , Ratas Wistar , Termogénesis/fisiologíaRESUMEN
Impaired angiogenesis is a hallmark of metabolically dysfunctional adipose tissue in obesity. However, the underlying mechanisms restricting angiogenesis within this context remain ill-defined. Here, we demonstrate that induced endothelial-specific depletion of the transcription factor Forkhead Box O1 (FoxO1) in male mice led to increased vascular density in adipose tissue. Upon high-fat diet feeding, endothelial cell FoxO1-deficient mice exhibited even greater vascular remodeling in the visceral adipose depot, which was paralleled with a healthier adipose tissue expansion, higher glucose tolerance and lower fasting glycemia concomitant with enhanced lactate levels. Mechanistically, FoxO1 depletion increased endothelial proliferative and glycolytic capacities by upregulating the expression of glycolytic markers, which may account for the improvements at the tissue level ultimately impacting whole-body glucose metabolism. Altogether, these findings reveal the pivotal role of FoxO1 in controlling endothelial metabolic and angiogenic adaptations in response to high-fat diet and a contribution of the endothelium to whole-body energy homeostasis.
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Endotelio Vascular/crecimiento & desarrollo , Endotelio Vascular/metabolismo , Proteína Forkhead Box O1/deficiencia , Obesidad/metabolismo , Animales , Dieta Alta en Grasa , Proteína Forkhead Box O1/metabolismo , Glucosa/metabolismo , Glucólisis , Homeostasis , Grasa Intraabdominal/irrigación sanguínea , Grasa Intraabdominal/metabolismo , Masculino , Ratones Noqueados , Microvasos/metabolismo , Modelos Biológicos , Músculo Esquelético/irrigación sanguínea , Obesidad/sangre , Tamaño de los Órganos , Especificidad de Órganos , Fenotipo , Triglicéridos/sangre , Regulación hacia Arriba , Remodelación VascularRESUMEN
This study investigated the effects of cold acclimation on circulating fibroblast growth factor 21 (FGF21) levels, as well as its production and signaling in classical brown and white adipose tissues. Male Wistar rats were cold (4°C) acclimatized for 7 days. Subsequently, liver, interscapular and aortic BAT (iBAT and aBAT), and the Sc Ing and epididymal (Epid) white adipose tissues were extracted. Cold acclimation significantly reduced circulating FGF21 and its liver expression. Conversely, FGF21 content increased in iBAT, aBAT and Sc Ing fat depots, along with the expressions of the Fgf21 receptor and the receptor co-factor ß-klotho. Cold acclimation increased FGF21 secretion from Sc Ing and Epid adipocytes, although only iBAT and Sc Ing fat depots enhanced ERK1/2 phosphorylation. These findings provide evidence that FGF21 acts in an autocrine/paracrine manner in iBAT and Sc Ing fat depots under cold-acclimating conditions and may contribute to driving depot-specific thermogenic adaptive responses.
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Tejido Adiposo/metabolismo , Factores de Crecimiento de Fibroblastos/sangre , Factores de Crecimiento de Fibroblastos/metabolismo , Termogénesis , Animales , Respuesta al Choque por Frío , Ingestión de Alimentos , Factores de Crecimiento de Fibroblastos/análisis , Hígado/metabolismo , Sistema de Señalización de MAP Quinasas , Masculino , Fosforilación , Ratas WistarRESUMEN
This study investigated the molecular and metabolic responses of the liver to cold-induced thermogenesis. To accomplish that, male Wistar rats were exposed to cold (4°C) for 7 days. Livers were then extracted and used for the determination of glucose and fatty acid oxidation, glycogen content, the expression and content of proteins involved in insulin signaling, as well as in the regulation of gluconeogenesis and de novo lipid synthesis. Despite being hyperphagic, cold-acclimated rats displayed normoglycemia with reduced insulinemia, which suggests improved whole-body insulin sensitivity. However, liver protein kinase B (AKT) and glycogen synthase kinase 3 (GSK3) phosphorylations were markedly reduced along with the expressions of the insulin receptor (IR) and its substrates IRS1 and IRS2, whereas glycogen synthase (GS) phosphorylation increased. Thus, major signaling steps of the glycogen synthesis pathway in the liver were inhibited. Furthermore, glucagonemia and hepatic glucose and fatty acid oxidation were increased, whereas liver glycogen content was reduced by cold acclimation. This was accompanied by significantly elevated expressions of the gluconeogenic transcription regulators CRTC2, PGC-1α, and FoxO1, as well as of major gluconeogenic enzymes (G6Pase, FBP1, and PEPCK). Conversely, phosphorylation and contents of AMP-activated protein kinase (AMPK) and acetyl-CoA carboxylase (ACC) and fatty acid synthase (FAS) content were markedly downregulated in livers of cold-acclimated rats. In conclusion, cold acclimation suppressed hepatic glycogen synthesis and promoted profound metabolic changes in the liver so the organ could sustain its ability to regulate whole-body glucose and lipid metabolism under conditions of high-energy demand in thermogenic tissues.