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Objective: To compare administration of the glucagon-like peptide-1 (GLP-1) analogue, exenatide, versus dietary supplementation with the omega-3 fatty acid-rich Calanus oil on obesity-induced alterations in mitochondrial respiration. Methods: Six-week-old female C57BL/6JOlaHSD mice were given high fat diet (HFD, 45% energy from fat) for 12 weeks to induce obesity. Thereafter, they were divided in three groups where one received exenatide (10 µg/kg/day) via subcutaneously implanted mini-osmotic pumps, a second group received 2% Calanus oil as dietary supplement, while the third group received HFD without any treatment. Animals were sacrificed after 8 weeks of treatment and tissues (skeletal muscle, liver, and white adipose tissue) were collected for measurement of mitochondrial respiratory activity by high-resolution respirometry, using an Oroboros Oxygraph-2k (Oroboros instruments, Innsbruck, Austria). Results: It was found that high-fat feeding led to a marked reduction of mitochondrial respiration in adipose tissue during all three states investigated - LEAK, OXPHOS and ETS. This response was to some extent attenuated by exenatide treatment, but not with Calanus oil treatment. High-fat feeding had no major effect on hepatic mitochondrial respiration, but exenatide treatment resulted in a significant increase in the various respiratory states in liver. Mitochondrial respiration in skeletal muscle was not significantly influenced by high-fat diet or any of the treatments. The precise evaluation of mitochondrial respiration considering absolute oxygen flux and ratios to assess flux control efficiency avoided misinterpretation of the results. Conclusions: Exenatide increased hepatic mitochondrial respiration in high-fat fed mice, but no clear beneficial effect was observed in skeletal muscle or fat tissue. Calanus oil did not negatively affect respiratory activity in these tissues, which maintains its potential as a dietary supplement, due to its previously reported benefits on cardiac function.
Assuntos
Ácidos Graxos Ômega-3 , Receptor do Peptídeo Semelhante ao Glucagon 1 , Camundongos , Animais , Feminino , Exenatida , Camundongos Endogâmicos C57BL , Obesidade/tratamento farmacológico , Obesidade/etiologia , Ácidos Graxos Ômega-3/farmacologia , Suplementos Nutricionais , RespiraçãoRESUMO
This review focuses on the role of adipose tissue in obese individuals in the development of metabolic diseases, and their consequences for metabolic and functional derangements in the heart. The general idea is that the expansion of adipocytes during the development of obesity gives rise to unhealthy adipose tissue, characterized by low-grade inflammation and the release of proinflammatory adipokines and fatty acids (FAs). This condition, in turn, causes systemic inflammation and elevated FA concentrations in the circulation, which links obesity to several pathologies, including impaired insulin signaling in cardiac muscle and a subsequent shift in myocardial substrate oxidation in favor of FAs and reduced cardiac efficiency. This review also argues that efforts to prevent obesity-related cardiometabolic disease should focus on anti-obesogenic strategies to restore normal adipose tissue metabolism.
RESUMO
Dietary supplementation with calanus oil, a novel wax ester-rich marine oil, has been shown to reduce adiposity in high-fat diet (HFD)-induced obese mice. Current evidence suggests that obesity and its comorbidities are intrinsically linked with unfavorable changes in the intestinal microbiome. Thus, in line with its antiobesity effect, we hypothesized that dietary supplementation with calanus oil should counteract the obesity-related deleterious changes in the gut microbiota. Seven-week-old female C57bl/6J mice received an HFD for 12â¯weeks to induce obesity followed by 8-week supplementation with 2% calanus oil. For comparative reasons, another group of mice was treated with exenatide, an antiobesogenic glucagon-like peptide-1 receptor agonist. Mice fed normal chow diet or nonsupplemented HFD for 20â¯weeks served as lean and obese controls, respectively. 16S rRNA gene sequencing was performed on fecal samples from the colon. HFD increased the abundance of the Lactococcus and Leuconostoc genera relative to normal chow diet, whereas abundances of Allobaculum and Oscillospira were decreased. Supplementation with calanus oil led to an apparent overrepresentation of Lactobacillus and Streptococcus and underrepresentation of Bilophila. Exenatide prevented the HFD-induced increase in Lactococcus and caused a decrease in the abundance of Streptococcus compared to the HFD group. Thus, HFD altered the gut microbiota composition in an unhealthy direction by increasing the abundance of proinflammatory genera while reducing those considered health-promoting. These obesity-induced changes were antagonized by both calanus oil and exenatide.
Assuntos
Dieta Hiperlipídica , Gorduras Insaturadas na Dieta/administração & dosagem , Suplementos Nutricionais , Microbioma Gastrointestinal , Obesidade/microbiologia , Óleos/administração & dosagem , Animais , Fármacos Antiobesidade/farmacologia , Bactérias/classificação , Bactérias/genética , Bactérias/crescimento & desenvolvimento , Colo/microbiologia , Exenatida/farmacologia , Fezes/microbiologia , Feminino , Metagenoma , Camundongos , Camundongos Endogâmicos C57BL , Obesidade/fisiopatologia , Obesidade/terapia , Aumento de PesoAssuntos
Doenças Cardiovasculares/tratamento farmacológico , Redes e Vias Metabólicas/efeitos dos fármacos , Doenças Cardiovasculares/metabolismo , Congressos como Assunto , Metabolismo Energético/efeitos dos fármacos , Coração/efeitos dos fármacos , Humanos , Contração Miocárdica/efeitos dos fármacos , Miocárdio/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Sociedades Médicas , Inibidores do Transportador 2 de Sódio-Glicose/farmacologia , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêuticoRESUMO
Obesity-induced insulin resistance and type 2 diabetes mellitus can ultimately result in various complications, including diabetic cardiomyopathy. In this case, cardiac dysfunction is characterized by metabolic disturbances such as impaired glucose oxidation and an increased reliance on fatty acid (FA) oxidation. Mitochondrial dysfunction has often been associated with the altered metabolic function in the diabetic heart, and may result from FA-induced lipotoxicity and uncoupling of oxidative phosphorylation. In this review, we address the metabolic changes in the diabetic heart, focusing on the loss of metabolic flexibility and cardiac mitochondrial function. We consider the alterations observed in mitochondrial substrate utilization, bioenergetics and dynamics, and highlight new areas of research which may improve our understanding of the cause and effect of cardiac mitochondrial dysfunction in diabetes. Finally, we explore how lifestyle (nutrition and exercise) and pharmacological interventions can prevent and treat metabolic and mitochondrial dysfunction in diabetes.
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Diabetes Mellitus Tipo 2/metabolismo , Cardiomiopatias Diabéticas/metabolismo , Resistência à Insulina , Animais , Diabetes Mellitus Tipo 2/patologia , Cardiomiopatias Diabéticas/etiologia , Cardiomiopatias Diabéticas/patologia , Ácidos Graxos/metabolismo , Humanos , Mitocôndrias Cardíacas/metabolismo , Mitocôndrias Cardíacas/patologiaRESUMO
Insulin resistance is an independent negative predictor of outcome after elective surgery and increases mortality among surgical patients in intensive care. The incretin hormone glucagon-like peptide-1 (GLP-1) potentiates glucose-induced insulin release from the pancreas but may also increase insulin sensitivity in skeletal muscle and directly suppress hepatic glucose release. Here, we investigated whether a perioperative infusion of GLP-1 could counteract the development of insulin resistance after surgery. Pigs were randomly assigned to three groups; surgery/control, surgery/GLP-1, and sham/GLP-1. Both surgery groups underwent major abdominal surgery. Whole-body glucose disposal (WGD) and endogenous glucose release (EGR) were assessed preoperatively and postoperatively using D-[6,6-2H2]-glucose infusion in combination with hyperinsulinemic euglycemic step-clamping. In the surgery/control group, peripheral insulin sensitivity (i.e., WGD) was reduced by 44% relative to preoperative conditions, whereas the corresponding decline was only 9% for surgery/GLP-1 (P < 0.05). Hepatic insulin sensitivity (i.e., EGR) remained unchanged in the surgery/control group but was enhanced after GLP-1 infusion in both surgery and sham animals (40% and 104%, respectively, both P < 0.05). Intraoperative plasma glucose increased in surgery/control (â¼20%) but remained unchanged in both groups receiving GLP-1 (P < 0.05). GLP-1 diminished an increase in postoperative glucagon levels but did not affect skeletal muscle glycogen or insulin signaling proteins after surgery. We show that GLP-1 improves intraoperative glycemic control, diminishes peripheral insulin resistance after surgery, and suppresses EGR. This study supports the use of GLP-1 to prevent development of postoperative insulin resistance.
Assuntos
Peptídeo 1 Semelhante ao Glucagon/administração & dosagem , Incretinas/administração & dosagem , Resistência à Insulina , Assistência Perioperatória/métodos , Procedimentos Cirúrgicos Operatórios/efeitos adversos , Animais , Glicemia , Avaliação Pré-Clínica de Medicamentos , Feminino , Técnica Clamp de Glucose , Glicogênio/metabolismo , Infusões Intravenosas , Insulina/sangue , Fígado/metabolismo , Músculo Esquelético/metabolismo , Período Perioperatório , Distribuição Aleatória , SuínosRESUMO
The aim of this study was to find out whether dietary supplementation with Calanus oil (a novel marine oil) or infusion of exenatide (an incretin mimetic) could counteract obesity-induced alterations in myocardial metabolism and improve postischemic recovery of left ventricular (LV) function. Female C57bl/6J mice received high-fat diet (HFD, 45% energy from fat) for 12 wk followed by 8-wk feeding with nonsupplemented HFD, HFD supplemented with 2% Calanus oil, or HFD plus exenatide infusion (10 µg·kg-1·day-1). A lean control group was included, receiving normal chow throughout the whole period. Fatty acid and glucose oxidation was measured in ex vivo perfused hearts during baseline conditions, while LV function was assessed with an intraventricular fluid-filled balloon before and after 20 min of global ischemia. HFD-fed mice receiving Calanus oil or exenatide showed less intra-abdominal fat deposition than mice receiving nonsupplemented HFD. Both treatments prevented the HFD-induced decline in myocardial glucose oxidation. Somewhat surprising, recovery of LV function was apparently better in hearts from mice fed nonsupplemented HFD relative to hearts from mice fed normal chow. More importantly however, postischemic recovery of hearts from mice receiving HFD with Calanus oil was superior to that of mice receiving nonsupplemented HFD and mice receiving HFD with exenatide, as expressed by better pressure development, contractility, and relaxation properties. In summary, dietary Calanus oil and administration of exenatide counteracted obesity-induced derangements of myocardial metabolism. Calanus oil also protected the heart from ischemia, which could have implications for the prevention of obesity-related cardiac disease. NEW & NOTEWORTHY This article describes for the first time that dietary supplementation with a low amount (2%) of a novel marine oil (Calanus oil) in mice is able to prevent the overreliance of fatty acid oxidation for energy production during obesity. The same effect was observed with infusion of the incretin mimetic, exanatide. The improvement in myocardial metabolism in Calanus oil-treated mice was accompanied by a significantly better recovery of cardiac performance following ischemia-reperfusion. Listen to this article's corresponding podcast at https://ajpheart.podbean.com/e/dietary-calanus-oil-energy-metabolism-and-cardiac-function/ .
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Copépodes , Metabolismo Energético , Traumatismo por Reperfusão Miocárdica/dietoterapia , Miocárdio/metabolismo , Obesidade/complicações , Óleos/administração & dosagem , Função Ventricular Esquerda , Ração Animal , Animais , Modelos Animais de Doenças , Exenatida/administração & dosagem , Ácidos Graxos/metabolismo , Feminino , Glucose/metabolismo , Incretinas/administração & dosagem , Preparação de Coração Isolado , Camundongos Endogâmicos C57BL , Contração Miocárdica , Traumatismo por Reperfusão Miocárdica/etiologia , Traumatismo por Reperfusão Miocárdica/metabolismo , Traumatismo por Reperfusão Miocárdica/fisiopatologia , Óleos/metabolismo , Recuperação de Função Fisiológica , Pressão VentricularRESUMO
Oil from the marine copepod, Calanus finmarchicus, which contains >86 % of fatty acids present as wax esters, is a novel source of n-3 fatty acids for human consumption. In a randomized, two-period crossover study, 18 healthy adults consumed 8 capsules providing 4 g of Calanus(®) Oil supplying a total of 260 mg EPA and 156 mg DHA primarily as wax esters, or 1 capsule of Lovaza(®) providing 465 mg EPA and 375 mg DHA as ethyl esters, each with an EPA- and DHA-free breakfast. Plasma EPA and DHA were measured over a 72 h period (t = 1, 2, 4, 6, 8, 10, 12, 24, 48, and 72 h). The positive incremental area under the curve over the 72 h test period (iAUC0-72 h) for both EPA and DHA was significantly different from zero (p < 0.0001) in both test conditions, with similar findings for the iAUC0-24 h and iAUC0-48 h, indicating the fatty acids were absorbed. There was no difference in the plasma iAUC0-72 h for EPA + DHA, or DHA individually, in response to Calanus Oil vs the ethyl ester condition; however, the iAUC0-48 h and iAUC0-72 h for plasma EPA in response to Calanus Oil were both significantly increased relative to the ethyl ester condition (iAUC0-48 h: 381 ± 31 vs 259 ± 39 µg*h/mL, p = 0.026; iAUC0-72 h: 514 ± 47 vs 313 ± 49 µg*h/mL, p = 0.009). These data demonstrate a novel wax ester rich marine oil is a suitable alternative source of EPA and DHA for human consumption.
Assuntos
Copépodes/química , Ácidos Docosa-Hexaenoicos/administração & dosagem , Ácido Eicosapentaenoico/administração & dosagem , Ceras/química , Adulto , Animais , Disponibilidade Biológica , Estudos Cross-Over , Suplementos Nutricionais , Ácidos Docosa-Hexaenoicos/farmacocinética , Esquema de Medicação , Ácido Eicosapentaenoico/farmacocinética , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Ceras/farmacocinética , Adulto JovemRESUMO
BACKGROUND: We have recently shown that Calanus oil, which is extracted from the marine copepod Calanus finmarchicus, reduces fat deposition, suppresses adipose tissue inflammation and improves insulin sensitivity in high fat-fed rodents. This study expands upon our previous observations by examining whether dietary supplementation with Calanus oil could antagonize angiotensin II (Ang II)-induced hypertension and ventricular remodeling in mice given a high fat diet (HFD). METHODS: C57BL/6J mice were initially subjected to 8 weeks of HFD with or without 2% (w/w) Calanus oil. Thereafter, animals within each group were randomized for the administration of either Ang II (1µg/kg/min) or saline for another two weeks, while still on the same dietary regimen. RESULTS: Ang II caused a marked decline in body and organ weights in mice receiving non-supplemented HFD, a response which was clearly attenuated in mice receiving Calanus oil supplementation. Furthermore, Ang II-induced elevation in blood pressure was also attenuated in the Calanus oil-supplemented group. As expected, infusion of Ang II produced hypertrophy and up-regulation of marker genes (mRNA level) of both hypertrophy and fibrosis in cardiac muscle, but this response was unaffected by dietary Calanus oil. Fibrosis and inflammation were up-regulated also in the aorta following Ang II infusion. However, the inflammatory response was blocked by Calanus oil supplementation. A final, and unexpected, finding was that dietary intake of Calanus oil caused a robust increase in the level of O-GlcNAcylation in cardiac tissue. CONCLUSION: These results suggest that dietary intake of oil from the marine copepod Calanus finmarchicus could be a beneficial addition to conventional hypertension treatment. The compound attenuates inflammation and the severe metabolic stress caused by Ang II infusion. Although the present study suggests that the anti-hypertensive effect of the oil (or its n-3 PUFAs constituents) is related to its anti-inflammatory action in the vessel wall, other mechanisms such as interaction with intracellular calcium mechanisms or a direct antagonistic effect on Ang II receptors should be examined.
Assuntos
Angiotensina II/efeitos adversos , Anti-Inflamatórios/administração & dosagem , Gorduras Insaturadas na Dieta/administração & dosagem , Hipertensão/dietoterapia , Animais , Anti-Inflamatórios/farmacologia , Aorta/efeitos dos fármacos , Peso Corporal/efeitos dos fármacos , Copépodes/química , Dieta Hiperlipídica , Gorduras Insaturadas na Dieta/farmacologia , Hipertensão/induzido quimicamente , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Obesos , Tamanho do Órgão/efeitos dos fármacos , Distribuição Aleatória , Resultado do TratamentoRESUMO
Development of acute insulin resistance represents a negative factor after surgery, but the underlying mechanisms are not fully understood. We investigated the postoperative changes in insulin sensitivity, mitochondrial function, enzyme activities, and release of reactive oxygen species (ROS) in skeletal muscle and liver in pigs on the 2nd postoperative day after major abdominal surgery. Peripheral and hepatic insulin sensitivity were assessed by D-[6,6-²H2]glucose infusion and hyperinsulinemic euglycemic step clamping. Surgical trauma elicited a decline in peripheral insulin sensitivity (â¼34%, P<0.01), whereas hepatic insulin sensitivity remained unchanged. Intramyofibrillar (IFM) and subsarcolemma mitochondria (SSM) isolated from skeletal muscle showed a postoperative decline in ADP-stimulated respiration (V(ADP)) for pyruvate (â¼61%, P<0.05, and â¼40%, P<0.001, respectively), whereas V(ADP) for glutamate and palmitoyl-L-carnitine (PC) was unchanged. Mitochondrial leak respiration with PC was increased in SSM (1.9-fold, P<0.05) and IFM (2.5-fold, P<0.05), indicating FFA-induced uncoupling. The activity of the pyruvate dehydrogenase complex (PDC) was reduced (â¼32%, P<0.01) and positively correlated to the decline in peripheral insulin sensitivity (r=0.748, P<0.05). All other mitochondrial enzyme activities were unchanged. No changes in mitochondrial function in liver were observed. Mitochondrial H2O2 and O2·â» emission was measured spectrofluorometrically, and H2O2 was increased in SSM, IFM, and liver mitochondria (â¼2.3-, â¼2.5-, and â¼2.3-fold, respectively, all P<0.05). We conclude that an impairment in skeletal muscle mitochondrial PDC activity and pyruvate oxidation capacity arises in the postoperative phase along with increased ROS emission, suggesting a link between mitochondrial function and development of acute postoperative insulin resistance.
Assuntos
Resistência à Insulina , Mitocôndrias Musculares/metabolismo , Músculo Esquelético/metabolismo , Estresse Oxidativo , Complicações Pós-Operatórias/metabolismo , Complexo Piruvato Desidrogenase/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Animais , Biomarcadores/sangue , Biomarcadores/metabolismo , Cruzamentos Genéticos , Técnica Clamp de Glucose , Fígado/enzimologia , Fígado/metabolismo , Mitocôndrias Hepáticas/enzimologia , Mitocôndrias Hepáticas/metabolismo , Mitocôndrias Musculares/enzimologia , Músculo Esquelético/enzimologia , Miofibrilas/enzimologia , Miofibrilas/metabolismo , Especificidade de Órgãos , Fosforilação Oxidativa , Consumo de Oxigênio , Complicações Pós-Operatórias/sangue , Complicações Pós-Operatórias/enzimologia , Ácido Pirúvico/metabolismo , Sarcolema/enzimologia , Sarcolema/metabolismo , Sus scrofaRESUMO
Insulin resistance is an important risk factor for the development of several cardiac pathologies, thus advocating strategies for restoring insulin sensitivity of the heart in these conditions. Omega-3 polyunsaturated fatty acids (ω-3 PUFAs), mainly eicosapentaenoic acid (EPA, C20:5n-3) and docosahexaenoic acid (DHA, C22:6n-3), have been shown to improve insulin sensitivity in insulin-sensitive tissues, but their direct effect on insulin signaling and metabolic parameters in the myocardium has not been reported previously. The aim of this study was therefore to examine the ability of EPA and DHA to prevent insulin resistance in isolated rat cardiomyocytes. Primary rat cardiomyocytes were made insulin resistant by 48 h incubation in high insulin (HI) medium. Parallel incubations were supplemented by 200 µM EPA or DHA. Addition of EPA or DHA to the medium prevented the induction of insulin resistance in cardiomyocytes by preserving the phosphorylation state of key proteins in the insulin signaling cascade and by preventing persistent relocation of fatty acid transporter CD36 to the sarcolemma. Only cardiomyocytes incubated in the presence of EPA, however, exhibited improvements in glucose and fatty acid uptake and cell shortening. We conclude that ω-3 PUFAs protect metabolic and functional properties of cardiomyocytes subjected to insulin resistance-evoking conditions.
Assuntos
Cardiotônicos/farmacologia , Ácidos Docosa-Hexaenoicos/farmacologia , Ácido Eicosapentaenoico/farmacologia , Metabolismo Energético/efeitos dos fármacos , Resistência à Insulina , Insulina/farmacologia , Miócitos Cardíacos/efeitos dos fármacos , Animais , Antígenos CD36/metabolismo , Células Cultivadas , Ácidos Docosa-Hexaenoicos/metabolismo , Ácido Eicosapentaenoico/metabolismo , Glucose/metabolismo , Masculino , Contração Miocárdica/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , Fosforilação , Transporte Proteico , Ratos Endogâmicos Lew , Sarcolema/efeitos dos fármacos , Sarcolema/metabolismo , Transdução de Sinais/efeitos dos fármacos , Fatores de TempoAssuntos
Cardiotônicos/farmacologia , Ativadores de Enzimas/farmacologia , Insuficiência Cardíaca/tratamento farmacológico , Infarto do Miocárdio/complicações , Miocárdio/enzimologia , Miosinas/metabolismo , Consumo de Oxigênio/efeitos dos fármacos , Ureia/análogos & derivados , Disfunção Ventricular Esquerda/tratamento farmacológico , Função Ventricular Esquerda/efeitos dos fármacos , Animais , Feminino , MasculinoRESUMO
The mechanisms contributing to multiorgan dysfunction during cardiogenic shock are poorly understood. Our goal was to characterize the microcirculatory and mitochondrial responses following ≥ 10 hours of severe left ventricular failure and cardiogenic shock. We employed a closed-chest porcine model of cardiogenic shock induced by left coronary microembolization (n = 12) and a time-matched control group (n = 6). Hemodynamics and metabolism were measured hourly by intravascular pressure catheters, thermodilution, arterial and organ specific blood gases. Echocardiography and assessment of the sublingual microcirculation by sidestream darkfield imaging were performed at baseline, 2 ± 1 and 13 ± 3 (mean ± SD) hours after coronary microembolization. Upon hemodynamic decompensation, cardiac, renal and hepatic mitochondria were isolated and evaluated by high-resolution respirometry. Low cardiac output, hypotension, oliguria and severe reductions in mixed-venous and hepatic O2 saturations were evident in cardiogenic shock. The sublingual total and perfused vessel densities were fully preserved throughout the experiments. Cardiac mitochondrial respiration was unaltered, whereas state 2, 3 and 4 respiration of renal and hepatic mitochondria were increased in cardiogenic shock. Mitochondrial viability (RCR; state 3/state 4) and efficiency (ADP/O ratio) were unaffected. Our study demonstrates that the microcirculation is preserved in a porcine model of untreated cardiogenic shock despite vital organ hypoperfusion. Renal and hepatic mitochondrial respiration is upregulated, possibly through demand-related adaptations, and the endogenous shock response is thus compensatory and protective, even after several hours of global hypoperfusion.
Assuntos
Choque Cardiogênico/fisiopatologia , Doença Aguda , Adaptação Fisiológica , Animais , Modelos Animais de Doenças , Masculino , Microcirculação/fisiologia , Mitocôndrias Cardíacas/fisiologia , Consumo de Oxigênio , Sus scrofaRESUMO
We showed previously that dietary supplementation with oil from the marine zooplankton Calanus finmarchicus (Calanus oil) attenuates obesity, inflammation, and glucose intolerance in mice. More than 80% of Calanus oil consists of wax esters, i.e., long-chain fatty alcohols linked to long-chain fatty acids. In the present study, we compared the metabolic effects of Calanus oil-derived wax esters (WE) with those of purified eicosapentaenoic acid (EPA) + docosahexaenoic acid (DHA) ethyl esters (E/D) in a mouse model of diet-induced obesity. C57BL/6J mice received a high-fat diet (HFD; 45% energy from fat). After 7 wk, the diet was supplemented with either 1% (wt:wt) WE or 0.2% (wt:wt) E/D. The amount of EPA + DHA in the E/D diet was matched to the total amount of n-3 (ω-3) polyunsaturated fatty acids (PUFAs) in the WE diet. A third group was given an unsupplemented HFD throughout the entire 27-wk feeding period. WE reduced body weight gain, abdominal fat, and liver triacylglycerol by 21%, 34%, and 52%, respectively, and significantly improved glucose tolerance and aerobic capacity. In abdominal fat depots, WE reduced macrophage infiltration by 74% and downregulated expression of proinflammatory genes (tumor necrosis factor-α, interleukin-6, and monocyte chemoattractant protein-1), whereas adiponectin expression was significantly upregulated. By comparison, E/D primarily suppressed the expression of proinflammatory genes but had less influence on glucose tolerance than WE. E/D affected obesity parameters, aerobic capacity, or adiponectin expression by <10%. These results show that the wax ester component of Calanus oil can account for the biologic effects shown previously for the crude oil. However, these effects cannot exclusively be ascribed to the content of n-3 PUFAs in the wax ester fraction.
Assuntos
Produtos Biológicos/uso terapêutico , Copépodes/química , Ácidos Graxos Ômega-3/uso terapêutico , Doenças Metabólicas/prevenção & controle , Obesidade/prevenção & controle , Ceras/uso terapêutico , Zooplâncton/química , Gordura Abdominal/efeitos dos fármacos , Gordura Abdominal/metabolismo , Adiponectina/genética , Adiponectina/metabolismo , Animais , Produtos Biológicos/farmacologia , Quimiocina CCL2/genética , Quimiocina CCL2/metabolismo , Dieta/efeitos adversos , Suplementos Nutricionais , Ácidos Docosa-Hexaenoicos/farmacologia , Ácidos Docosa-Hexaenoicos/uso terapêutico , Regulação para Baixo , Ácido Eicosapentaenoico/farmacologia , Ácido Eicosapentaenoico/uso terapêutico , Ésteres/farmacologia , Ésteres/uso terapêutico , Ácidos Graxos Ômega-3/farmacologia , Expressão Gênica/efeitos dos fármacos , Intolerância à Glucose/etiologia , Intolerância à Glucose/prevenção & controle , Inflamação/genética , Inflamação/metabolismo , Interleucina-6/genética , Interleucina-6/metabolismo , Fígado/efeitos dos fármacos , Fígado/metabolismo , Macrófagos/efeitos dos fármacos , Masculino , Doenças Metabólicas/etiologia , Camundongos , Camundongos Endogâmicos C57BL , Obesidade/etiologia , Obesidade/genética , Obesidade/metabolismo , Resistência Física/efeitos dos fármacos , Triglicerídeos/metabolismo , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/metabolismo , Ceras/farmacologia , Aumento de Peso/efeitos dos fármacosRESUMO
The aim of the present study was to investigate the effects of oil extracted from the zooplankton Calanus finmarchicus (Calanus oil) on diet-induced obesity and obesity-related disorders in mice. C57BL/6J mice fed a high-fat diet (HFD, 45% energy from fat) exhibited increased body weight and abdominal fat accumulation as well as impaired glucose tolerance compared with mice fed a normal chow diet (10% energy from fat). Supplementing the HFD with 1.5% (w/w) Calanus oil reduced body-weight gain, abdominal fat accumulation and hepatic steatosis by 16, 27 and 41%, respectively, and improved glucose tolerance by 16%. Calanus oil supplementation reduced adipocyte size and increased the mRNA expression of adiponectin in adipose tissue. It also reduced macrophage infiltration by more than 70%, accompanied by reduced mRNA expression of pro-inflammatory cytokines (TNF-α, IL-6 and monocyte chemotactic protein-1). The effects of Calanus oil were not only preventive, but also therapeutic, as the oil proved to be beneficial, regardless of whether the supplementation was started before or after the onset of obesity and glucose intolerance. Although the present study cannot pinpoint the active component(s) of the oil, there is reason to believe that the n-3 fatty acids EPA and DHA and/or antioxidants are responsible for its beneficial effects. It should be noted that the concentration of n-3 fatty acids in the Calanus oil diet was considerably lower than the concentrations used in similar studies reporting beneficial effects on obesity and obesity-related abnormalities.
Assuntos
Gordura Abdominal/efeitos dos fármacos , Produtos Biológicos/uso terapêutico , Copépodes/química , Intolerância à Glucose/tratamento farmacológico , Obesidade/tratamento farmacológico , Aumento de Peso/efeitos dos fármacos , Zooplâncton/química , Gordura Abdominal/metabolismo , Adiponectina/genética , Adiponectina/metabolismo , Tecido Adiposo/citologia , Tecido Adiposo/efeitos dos fármacos , Tecido Adiposo/metabolismo , Animais , Antioxidantes/farmacologia , Antioxidantes/uso terapêutico , Produtos Biológicos/farmacologia , Doenças Cardiovasculares/etiologia , Doenças Cardiovasculares/prevenção & controle , Citocinas/genética , Citocinas/metabolismo , Dieta Hiperlipídica/efeitos adversos , Suplementos Nutricionais , Ácidos Graxos Ômega-3/farmacologia , Ácidos Graxos Ômega-3/uso terapêutico , Fígado Gorduroso/etiologia , Fígado Gorduroso/metabolismo , Fígado Gorduroso/prevenção & controle , Intolerância à Glucose/etiologia , Intolerância à Glucose/metabolismo , Macrófagos/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Obesos , Obesidade/complicações , Obesidade/metabolismo , RNA Mensageiro/metabolismoRESUMO
Although exercise reduces several cardiovascular risk factors associated with obesity/diabetes, the metabolic effects of exercise on the heart are not well-known. This study was designed to investigate whether high-intensity interval training (HIT) is superior to moderate-intensity training (MIT) in counteracting obesity-induced impairment of left ventricular (LV) mechanoenergetics and function. C57BL/6J mice with diet-induced obesity (DIO mice) displaying a cardiac phenotype with altered substrate utilization and impaired mechanoenergetics were subjected to a sedentary lifestyle or 8-10 weeks of isocaloric HIT or MIT. Although both modes of exercise equally improved aerobic capacity and reduced obesity, only HIT improved glucose tolerance. Hearts from sedentary DIO mice developed concentric LV remodeling with diastolic and systolic dysfunction, which was prevented by both HIT and MIT. Both modes of exercise also normalized LV mechanical efficiency and mechanoenergetics. These changes were associated with altered myocardial substrate utilization and improved mitochondrial capacity and efficiency, as well as reduced oxidative stress, fibrosis, and intracellular matrix metalloproteinase 2 content. As both modes of exercise equally ameliorated the development of diabetic cardiomyopathy by preventing LV remodeling and mechanoenergetic impairment, this study advocates the therapeutic potential of physical activity in obesity-related cardiac disorders.
Assuntos
Ventrículos do Coração/fisiopatologia , Obesidade/fisiopatologia , Condicionamento Físico Animal/fisiologia , Função Ventricular/fisiologia , Animais , Dieta Hiperlipídica/efeitos adversos , Masculino , Metaloproteinase 2 da Matriz/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Mitocôndrias/fisiologia , Miocárdio/metabolismo , Obesidade/etiologia , Obesidade/metabolismo , Estresse Oxidativo/fisiologiaRESUMO
Transgenic mice with cardiac-specific expression of a peptide inhibitor of G protein-coupled receptor kinase (GRK)3 [transgenic COOH-terminal GRK3 (GRK3ct) mice] display myocardial hypercontractility without hypertrophy and enhanced α(1)-adrenergic receptor signaling. A role for GRK3 in the pathogenesis of heart failure (HF) has not been investigated, but inhibition of its isozyme, GRK2, has been beneficial in several HF models. Here, we tested whether inhibition of GRK3 modulated evolving cardiac hypertrophy and dysfunction after pressure overload. Weight-matched male GRK3ct transgenic and nontransgenic littermate control (NLC) mice subjected to chronic pressure overload by abdominal aortic banding (AB) were compared with sham-operated (SH) mice. At 6 wk after AB, a significant increase of cardiac mass consistent with induction of hypertrophy was found, but no differences between GRK3ct-AB and NLC-AB mice were discerned. Simultaneous left ventricular (LV) pressure-volume analysis of electrically paced, ex vivo perfused working hearts revealed substantially reduced systolic and diastolic function in NLC-AB mice (n = 7), which was completely preserved in GRK3ct-AB mice (n = 7). An additional cohort was subjected to in vivo cardiac catheterization and LV pressure-volume analysis at 12 wk after AB. NLC-AB mice (n = 11) displayed elevated end-diastolic pressure (8.5 ± 3.1 vs. 2.9 ± 1.2 mmHg, P < 0.05), reduced cardiac output (3,448 ± 323 vs. 4,488 ± 342 µl/min, P < 0.05), and reduced dP/dt(max) and dP/dt(min) (both P < 0.05) compared with GRK3ct-AB mice (n = 16), corroborating the preserved cardiac structure and function observed in GRK3ct-AB hearts assessed ex vivo. Increased cardiac mass and myocardial mRNA expression of ß-myosin heavy chain confirmed the similar induction of cardiac hypertrophy in both AB groups, but only NLC-AB hearts displayed significantly elevated mRNA levels of brain natriuretic peptide and myocardial collagen contents as well as reduced ß(1)-adrenergic receptor responsiveness to isoproterenol, indicating increased LV wall stress and the transition to HF. Inhibition of cardiac GRK3 in mice does not alter the hypertrophic response but attenuates cardiac dysfunction and HF after chronic pressure overload.
Assuntos
Quinase 3 de Receptor Acoplado a Proteína G/fisiologia , Cardiopatias/tratamento farmacológico , Hipertensão/complicações , Miócitos Cardíacos/fisiologia , Adenilil Ciclases/metabolismo , Agonistas Adrenérgicos beta/farmacologia , Animais , Cardiomegalia/etiologia , Cardiomegalia/patologia , Fibrose Endomiocárdica/patologia , Quinase 3 de Receptor Acoplado a Proteína G/antagonistas & inibidores , Quinase 3 de Receptor Acoplado a Proteína G/genética , Cardiopatias/etiologia , Cardiopatias/fisiopatologia , Insuficiência Cardíaca/prevenção & controle , Imuno-Histoquímica , Isoproterenol/farmacologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos CBA , Miocárdio/enzimologia , Miocárdio/metabolismo , Miócitos Cardíacos/enzimologia , RNA Mensageiro/biossíntese , RNA Mensageiro/genética , Função Ventricular Esquerda/fisiologiaRESUMO
Tetradecylthioacetic acid (TTA) is a novel peroxisome proliferator-activated receptor (PPAR) ligand with marked hypolipidemic and insulin-sensitizing effects in obese models. TTA has recently been shown to attenuate dyslipidemia in patients with type 2 diabetes, corroborating the potential for TTA in antidiabetic therapy. In a recent study on normal mice, we showed that TTA increased myocardial fatty acid (FA) oxidation, which was associated with decreased cardiac efficiency and impaired postischemic functional recovery. The aim of the present study was, therefore, to elucidate the effects of TTA treatment (0.5%, 8 days) on cardiac metabolism and function in a hyperlipidemic type 2 diabetic model. We found that TTA treatment increased myocardial FA oxidation, not only in nondiabetic (db/+) mice but also in diabetic (db/db) mice, despite a clear lipid-lowering effect. Although TTA had deleterious effects in hearts from nondiabetic mice (decreased efficiency and impaired mitochondrial respiratory capacity), these effects were not observed in db/db hearts. In db/db hearts, TTA improved ischemic tolerance, an effect that is most likely related to the antioxidant property of TTA. The present study strongly advocates the need for investigation of the cardiac effects of PPAR ligands used in antidiabetic/hypolipidemic therapy, because of their pleiotropic properties.
Assuntos
Antioxidantes/farmacologia , Cardiotônicos/farmacologia , Diabetes Mellitus Tipo 2/metabolismo , Coração/efeitos dos fármacos , Receptores Ativados por Proliferador de Peroxissomo , Sulfetos/farmacologia , Animais , Antioxidantes/uso terapêutico , Cardiotônicos/uso terapêutico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Modelos Animais de Doenças , Transporte de Elétrons/efeitos dos fármacos , Ácidos Graxos/metabolismo , Hiperlipidemias/tratamento farmacológico , Hiperlipidemias/metabolismo , Ligantes , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Mutantes , Miocárdio/metabolismo , Oxirredução , Estresse Oxidativo/efeitos dos fármacos , Sulfetos/uso terapêuticoRESUMO
The aim of the present study was to evaluate the underlying processes involved in the oxygen wasting induced by inotropic drugs and acute and chronic elevation of fatty acid (FA) supply, using unloaded perfused mouse hearts from normal and type 2 diabetic (db/db) mice. We found that an acute elevation of the FA supply in normal hearts, as well as a chronic (in vivo) exposure to elevated FA as in db/db hearts, increased myocardial oxygen consumption (MVo2(unloaded)) due to increased oxygen cost for basal metabolism and for excitation-contraction (EC) coupling. Isoproterenol stimulation, on top of a high FA supply, led to an additive increase in MVo2(unloaded), because of a further increase in oxygen cost for EC coupling. In db/db hearts, the acute elevation of FA did not further increase MVo2. Since the elevation in the FA supply is accompanied by increased rates of myocardial FA oxidation, the present study compared MVo2 following increased FA load versus FA oxidation rate by exposing normal hearts to normal and high FA concentration (NF and HF, respectively) and to compounds that either stimulate (GW-610742) or inhibit [dichloroacetate (DCA)] FA oxidation. While HF and NF + GW-610742 increased FA oxidation to the same extent, only HF increased MVo2(unloaded). Although DCA counteracted the HF-induced increase in FA oxidation, DCA did not reduce MVo2(unloaded). Thus, in normal hearts, acute FA-induced oxygen waste is 1) due to an increase in the oxygen cost for both basal metabolism and EC coupling and 2) not dependent on the myocardial FA oxidation rate per se, but on processes initiated by the presence of FAs. In diabetic hearts, chronic exposure to elevated circulating FAs leads to adaptations that afford protection against the detrimental effect of an acute FA load, suggesting different underlying mechanisms behind the increased MVo2 following acute and chronic FA load.
Assuntos
Acoplamento Excitação-Contração/efeitos dos fármacos , Ácidos Graxos/farmacologia , Coração/efeitos dos fármacos , Coração/fisiologia , Oxigênio/metabolismo , Animais , Metabolismo Basal/efeitos dos fármacos , Metabolismo Basal/fisiologia , Cardiotônicos/farmacologia , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/fisiopatologia , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Acoplamento Excitação-Contração/fisiologia , Isoproterenol/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Contração Miocárdica/efeitos dos fármacos , Contração Miocárdica/fisiologia , Consumo de Oxigênio/efeitos dos fármacos , Consumo de Oxigênio/fisiologiaRESUMO
BACKGROUND: Speckle-tracking echocardiography (STE) can be used to quantify wall strain in 3 dimensions and thus has the potential to improve the identification of hypokinetic but viable myocardium on dobutamine stress echocardiography (DSE). However, if different myocardial layers respond heterogeneously, STE-DSE will have to be standardized according to strain dimension and the positioning of the region of interest. Therefore, the aim of this study was to create a high-resolution model for ejection time (ET) strain and tissue flow in 4 myocardial layers at rest, during hypoperfusion, and during dobutamine challenge to assess the ability of STE-DSE to detect deformation and functional improvement in various layers of the myocardium. METHODS: In 10 open chest pigs, the left anterior descending coronary artery was constricted to a constant stenosis, resulting in 35% initial flow reduction. Fluorescent microspheres were used to measure tissue flow. High-resolution echocardiography was performed epicardially to calculate ET strain in 4 myocardial layers in the radial, longitudinal, and circumferential directions using speckle-tracking software. Images were obtained at rest, during left anterior descending coronary artery constriction (hypoperfusion), and during a subsequent dobutamine stress period. RESULTS: Dobutamine stress at constant coronary stenosis increased flow in all layers. ET strain increased predominantly in the midmyocardial layers in the longitudinal and circumferential directions, whereas subendocardial strain did not improve in either direction. CONCLUSION: Dobutamine stress influences ET strain differently in the various axes and layers of the myocardium and only partially in correspondence to tissue flow. Longitudinal and circumferential functional reserve opens the potential for the specific detection of midsubendocardial viable tissue by high-resolution STE.