RESUMO
CONTEXT: Elevating nicotinamide adenine dinucleotide (NAD+) levels systemically improves metabolic health, which can be accomplished via nicotinamide riboside (NR). Previously, it was demonstrated that NR supplementation in high-fat-diet (HFD)-fed mice decreased weight gain, normalized glucose metabolism, and enhanced cold tolerance. OBJECTIVE: Because brown adipose tissue (BAT) is a major source of thermogenesis, we hypothesize that NR stimulates BAT in mice and humans. DESIGN AND INTERVENTION: HFD-fed C56BL/6J mice were supplemented with 400 mg/kg/day NR for 4 weeks and subsequently exposed to cold. In vitro primary adipocytes derived from human BAT biopsies were pretreated with 50 µM or 500 µM NR before measuring mitochondrial uncoupling. Human volunteers (45-65 years; body mass index, 27-35 kg/m2) were supplemented with 1000 mg/day NR for 6 weeks to determine whether BAT activity increased, as measured by [18F]FDG uptake via positron emission tomography-computed tomography (randomized, double blinded, placebo-controlled, crossover study with NR supplementation). RESULTS: NR supplementation in HFD-fed mice decreased adipocyte cell size in BAT. Cold exposure further decreased adipocyte cell size on top of that achieved by NR alone independent of ex vivo lipolysis. In adipocytes derived from human BAT, NR enhanced in vitro norepinephrine-stimulated mitochondrial uncoupling. However, NR supplementation in human volunteers did not alter BAT activity or cold-induced thermogenesis. CONCLUSIONS: NR stimulates in vitro human BAT but not in vivo BAT in humans. Our research demonstrates the need for further translational research to better understand the differences in NAD+ metabolism in mouse and human.
Assuntos
Tecido Adiposo Marrom/efeitos dos fármacos , Niacinamida/análogos & derivados , Compostos de Piridínio/farmacologia , Receptores Adrenérgicos/metabolismo , Adipócitos/metabolismo , Tecido Adiposo Marrom/metabolismo , Tecido Adiposo Marrom/fisiologia , Adrenérgicos/farmacologia , Idoso , Animais , Células Cultivadas , Estudos Cross-Over , Método Duplo-Cego , Metabolismo Energético/efeitos dos fármacos , Feminino , Humanos , Lipólise/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade , Niacinamida/farmacologia , Cultura Primária de Células , Termogênese/efeitos dos fármacosRESUMO
Creatine availability in adipose tissue has been shown to have profound effects on thermogenesis and energy balance in mice. However, whether dietary creatine supplementation affects brown adipose tissue (BAT) activation in humans is unclear. In the present study, we report the results of a double-blind, randomized, placebo-controlled, cross-over trial (NCT04086381) in which 14 young, healthy, vegetarian adults, who are characterized by low creatine levels, received 20 g of creatine monohydrate per day or placebo. Participants were eligible if they met the following criteria: male or female, white, aged 18-30 years, consuming a vegetarian diet (≥6 months) and body mass index 20-25 kg m-2. BAT activation after acute cold exposure was determined by calculating standard uptake values (SUVs) acquired by [18F]fluorodeoxyglucose positron emission tomography-magnetic resonance imaging. BAT volume (-31.32 (19.32) SUV (95% confidence interval (CI) -73.06, 10.42; P = 0.129)), SUVmean (-0.34 (0.29) SUV (95% CI -0.97, 0.28; P = 0.254)) and SUVmax (-2.49 (2.64) SUV (95% CI -8.20, 3.21; P = 0.362)) following acute cold exposure were similar between placebo and creatine supplementation. No side effects of creatine supplementation were reported; one participant experienced bowel complaints during placebo, which resolved without intervention. Our data show that creatine monohydrate supplementation in young, healthy, lean, vegetarian adults does not enhance BAT activation after acute cold exposure.
Assuntos
Tecido Adiposo Marrom/metabolismo , Creatina/farmacologia , Vegetarianos , Tecido Adiposo Marrom/efeitos dos fármacos , Adolescente , Adulto , Composição Corporal , Índice de Massa Corporal , Temperatura Baixa , Estudos Cross-Over , Suplementos Nutricionais , Método Duplo-Cego , Feminino , Fluordesoxiglucose F18 , Humanos , Masculino , Mitocôndrias Musculares/efeitos dos fármacos , Mitocôndrias Musculares/metabolismo , Tomografia por Emissão de Pósitrons , Compostos Radiofarmacêuticos , Adulto JovemRESUMO
BACKGROUND: Low carnitine status may underlie the development of insulin resistance and metabolic inflexibility. Intravenous lipid infusion elevates plasma free fatty acid (FFA) concentration and is a model for simulating insulin resistance and metabolic inflexibility in healthy, insulin sensitive volunteers. Here, we hypothesized that co-infusion of L-carnitine may alleviate lipid-induced insulin resistance and metabolic inflexibility. METHODS: In a randomized crossover trial, eight young healthy volunteers underwent hyperinsulinemic-euglycemic clamps (40mU/m2/min) with simultaneous infusion of saline (CON), Intralipid (20%, 90mL/h) (LIPID), or Intralipid (20%, 90mL/h) combined with L-carnitine infusion (28mg/kg) (LIPID+CAR). Ten volunteers were randomized for the intervention arms (CON, LIPID and LIPID+CAR), but two dropped-out during the study. Therefore, eight volunteers participated in all three intervention arms and were included for analysis. RESULTS: L-carnitine infusion elevated plasma free carnitine availability and resulted in a more pronounced increase in plasma acetylcarnitine, short-, medium-, and long-chain acylcarnitines compared to lipid infusion, however no differences in skeletal muscle free carnitine or acetylcarnitine were found. Peripheral insulin sensitivity and metabolic flexibility were blunted upon lipid infusion compared to CON but L-carnitine infusion did not alleviate this. CONCLUSION: Acute L-carnitine infusion could not alleviated lipid-induced insulin resistance and metabolic inflexibility and did not alter skeletal muscle carnitine availability. Possibly, lipid-induced insulin resistance may also have affected carnitine uptake and may have blunted the insulin-induced carnitine storage in muscle. Future studies are needed to investigate this.
Assuntos
Carnitina/administração & dosagem , Ácidos Graxos não Esterificados/sangue , Ácidos Graxos não Esterificados/metabolismo , Resistência à Insulina/fisiologia , Lipídeos/administração & dosagem , Adulto , Carnitina/análogos & derivados , Carnitina/sangue , Estudos Cross-Over , Emulsões/administração & dosagem , Humanos , Bombas de Infusão , Insulina/sangue , Insulina/metabolismo , Masculino , Músculo Esquelético/efeitos dos fármacos , Músculo Esquelético/metabolismo , Fosfolipídeos/administração & dosagem , Óleo de Soja/administração & dosagem , Adulto JovemRESUMO
BACKGROUND: Effects of resveratrol on metabolic health have been studied in several short-term human clinical trials, with conflicting results. Next to dose, the duration of the clinical trials may explain the lack of effect in some studies, but long-term studies are still limited. OBJECTIVES: The objective of this study was to investigate the effects of 6-mo resveratrol supplementation on metabolic health outcome parameters. METHODS: Forty-one overweight men and women (BMI: 27-35 kg/m2; aged 40-70 y) completed the study. In this parallel-group, double-blind clinical trial, participants were randomized to receive either 150 mg/d of resveratrol (n = 20) or placebo (n = 21) for 6 mo. The primary outcome of the study was insulin sensitivity, using the Matsuda index. Secondary outcome measures were intrahepatic lipid (IHL) content, body composition, resting energy metabolism, blood pressure, plasma markers, physical performance, quality of life, and quality of sleep. Postintervention differences between the resveratrol and placebo arms were evaluated by ANCOVA adjusting for corresponding preintervention variables. RESULTS: Preintervention, no differences were observed between the 2 treatment arms. Insulin sensitivity was not affected after 6 mo of resveratrol treatment (adjusted mean Matsuda index: 5.18 ± 0.35 in the resveratrol arm compared with 5.50 ± 0.34 in the placebo arm), although there was a significant difference in postintervention glycated hemoglobin (HbA1c) between the arms (P = 0.007). The adjusted means showed that postintervention HbA1c was lower on resveratrol (35.8 ± 0.43 mmol/mol) compared with placebo (37.6 ± 0.44 mmol/mol). No postintervention differences were found in IHL, body composition, blood pressure, energy metabolism, physical performance, or quality of life and sleep between treatment arms. CONCLUSIONS: After 6 mo of resveratrol supplementation, insulin sensitivity was unaffected in the resveratrol arm compared with the placebo arm. Nonetheless, HbA1c was lower in overweight men and women in the resveratrol arm. This trial was registered at Clinicaltrials.gov as NCT02565979.
Assuntos
Resistência à Insulina , Sobrepeso/metabolismo , Resveratrol/administração & dosagem , Adulto , Idoso , Composição Corporal , Suplementos Nutricionais , Metabolismo Energético , Feminino , Hemoglobinas Glicadas/análise , Humanos , Masculino , Pessoa de Meia-Idade , Desempenho Físico Funcional , Qualidade de VidaRESUMO
AIM: Heat exposure has been indicated to positively affect glucose metabolism. An involvement of heat shock protein 72 (HSP72) in the enhancement of insulin sensitivity upon heat exposure has been previously suggested. Here, we performed an intervention study exploring the effect of passive heat acclimation (PHA) on glucose metabolism and intracellular (a) HSP72 concentrations in overweight humans. METHODS: Eleven non-diabetic overweight (BMI 27-35 kg/m2 ) participants underwent 10 consecutive days of PHA (4-6 h/day, 34.4 ± 0.2°C, 22.8 ± 2.7%RH). Before and after PHA, whole-body insulin sensitivity was assessed using a one-step hyperinsulinaemic-euglycaemic clamp, skeletal muscle biopsies were taken to measure intracellular iHSP72, energy expenditure and substrate oxidation were measured using indirect calorimetry and blood samples were drawn to assess markers of metabolic health. Thermophysiological adaptations were measured during a temperature ramp protocol before and after PHA. RESULTS: Despite a lack of change in iHSP72, 10 days of PHA reduced basal (9.7 ± 1.4 pre- vs 8.4 ± 2.1 µmol · kg-1 · min-1 post-PHA, P = .038) and insulin-stimulated (2.1 ± 0.9 pre- vs 1.5 ± 0.8 µmol · kg-1 · min-1 post-PHA, P = .005) endogenous glucose production (EGP) and increased insulin suppression of EGP (78.5 ± 9.7% pre- vs 83.0 ± 7.9% post-PHA, P = .028). Consistently, fasting plasma glucose (6.0 ± 0.5 pre- vs 5.8 ± 0.4 mmol/L post-PHA, P = .013) and insulin concentrations (97 ± 55 pre- vs 84 ± 49 pmol/L post-PHA, P = .026) decreased significantly. Moreover, fat oxidation increased, and free fatty acids as well as cholesterol concentrations and mean arterial pressure decreased after PHA. CONCLUSION: Our results show that PHA for 10 days improves glucose metabolism and enhances fat metabolism, without changes in iHSP72. Further exploration of the therapeutic role of heat in cardio-metabolic disorders should be considered.
Assuntos
Glucose/metabolismo , Hipertermia Induzida , Resistência à Insulina , Idoso , Glicemia , Diabetes Mellitus Tipo 2 , Técnica Clamp de Glucose , Humanos , Insulina , Pessoa de Meia-Idade , SobrepesoRESUMO
BACKGROUND: Nicotinamide riboside (NR) is an NAD+ precursor that boosts cellular NAD+ concentrations. Preclinical studies have shown profound metabolic health effects after NR supplementation. OBJECTIVES: We aimed to investigate the effects of 6 wk NR supplementation on insulin sensitivity, mitochondrial function, and other metabolic health parameters in overweight and obese volunteers. METHODS: A randomized, double-blinded, placebo-controlled, crossover intervention study was conducted in 13 healthy overweight or obese men and women. Participants received 6 wk NR (1000 mg/d) and placebo supplementation, followed by broad metabolic phenotyping, including hyperinsulinemic-euglycemic clamps, magnetic resonance spectroscopy, muscle biopsies, and assessment of ex vivo mitochondrial function and in vivo energy metabolism. RESULTS: Markers of increased NAD+ synthesis-nicotinic acid adenine dinucleotide and methyl nicotinamide-were elevated in skeletal muscle after NR compared with placebo. NR increased body fat-free mass (62.65% ± 2.49% compared with 61.32% ± 2.58% in NR and placebo, respectively; change: 1.34% ± 0.50%, P = 0.02) and increased sleeping metabolic rate. Interestingly, acetylcarnitine concentrations in skeletal muscle were increased upon NR (4558 ± 749 compared with 3025 ± 316 pmol/mg dry weight in NR and placebo, respectively; change: 1533 ± 683 pmol/mg dry weight, P = 0.04) and the capacity to form acetylcarnitine upon exercise was higher in NR than in placebo (2.99 ± 0.30 compared with 2.40 ± 0.33 mmol/kg wet weight; change: 0.53 ± 0.21 mmol/kg wet weight, P = 0.01). However, no effects of NR were found on insulin sensitivity, mitochondrial function, hepatic and intramyocellular lipid accumulation, cardiac energy status, cardiac ejection fraction, ambulatory blood pressure, plasma markers of inflammation, or energy metabolism. CONCLUSIONS: NR supplementation of 1000 mg/d for 6 wk in healthy overweight or obese men and women increased skeletal muscle NAD+ metabolites, affected skeletal muscle acetylcarnitine metabolism, and induced minor changes in body composition and sleeping metabolic rate. However, no other metabolic health effects were observed.This trial was registered at clinicaltrials.gov as NCT02835664.
Assuntos
Acetilcarnitina/metabolismo , Composição Corporal/efeitos dos fármacos , Músculo Esquelético/metabolismo , Niacinamida/análogos & derivados , Obesidade/tratamento farmacológico , Sobrepeso/tratamento farmacológico , Idoso , Suplementos Nutricionais/análise , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Músculo Esquelético/efeitos dos fármacos , NAD/biossíntese , Niacinamida/administração & dosagem , Obesidade/metabolismo , Obesidade/fisiopatologia , Sobrepeso/metabolismo , Sobrepeso/fisiopatologia , Compostos de PiridínioRESUMO
BACKGROUND: Type 2 diabetes patients and individuals at risk of developing diabetes are characterized by metabolic inflexibility and disturbed glucose homeostasis. Low carnitine availability may contribute to metabolic inflexibility and impaired glucose tolerance. Here, we investigated whether carnitine supplementation improves metabolic flexibility and insulin sensitivity in impaired glucose tolerant (IGT) volunteers. METHODS: Eleven IGT- volunteers followed a 36-day placebo- and L-carnitine treatment (2â¯g/day) in a randomised, placebo-controlled, double blind crossover design. A hyperinsulinemic-euglycemic clamp (40 mU/m2/min), combined with indirect calorimetry (ventilated hood) was performed to determine insulin sensitivity and metabolic flexibility. Furthermore, metabolic flexibility was assessed in response to a high-energy meal. Skeletal muscle acetylcarnitine concentrations were measured in vivo using long echo time proton magnetic resonance spectroscopy (1H-MRS, TE=500â¯ms) in the resting state (7:00AM and 5:00PM) and after a 30-min cycling exercise. Twelve normal glucose tolerant (NGT) volunteers were included without any intervention as control group. RESULTS: Metabolic flexibility of IGT-subjects completely restored towards NGT control values upon carnitine supplementation, measured during a hyperinsulinemic-euglycemic clamp and meal test. In muscle, carnitine supplementation enhanced the increase in resting acetylcarnitine concentrations over the day (delta 7:00 AM versus 5:00 PM) in IGT-subjects. Furthermore, carnitine supplementation increased post-exercise acetylcarnitine concentrations and reduced long-chain acylcarnitine species in IGT-subjects, suggesting the stimulation of a more complete fat oxidation in muscle. Whole-body insulin sensitivity was not affected. CONCLUSION: Carnitine supplementation improves acetylcarnitine formation and rescues metabolic flexibility in IGT-subjects. Future research should investigate the potential of carnitine in prevention/treatment of type 2 diabetes.
Assuntos
Acetilcarnitina/metabolismo , Carnitina/farmacologia , Suplementos Nutricionais , Voluntários Saudáveis , Músculo Esquelético/metabolismo , Acetilcarnitina/sangue , Composição Corporal/efeitos dos fármacos , Carnitina/sangue , Feminino , Teste de Tolerância a Glucose , Glicogênio/metabolismo , Humanos , Hiperinsulinismo/sangue , Resistência à Insulina , Cinética , Masculino , Metaboloma , Pessoa de Meia-Idade , Consumo de Oxigênio/efeitos dos fármacosRESUMO
OBJECTIVE: Resveratrol supplementation improves metabolic health in healthy obese men, but not in patients with type 2 diabetes (T2D) when given as add-on therapy. Therefore, we examined whether resveratrol can enhance metabolic health in men at risk of developing T2D. Additionally, we examined if resveratrol can stimulate brown adipose tissue (BAT). METHODS: Thirteen male first degree relatives (FDR) of patients with T2D received resveratrol (150 mg/day) and placebo for 30 days in a randomized, placebo controlled, cross-over trial. RESULTS: Resveratrol significantly improved ex vivo muscle mitochondrial function on a fatty acid-derived substrate. However, resveratrol did not improve insulin sensitivity, expressed as the rate of glucose disposal during a two-step hyperinsulinemic-euglycemic clamp. Also, intrahepatic and intramyocellular lipid content, substrate utilization, energy metabolism, and cold-stimulated 18F-FDG glucose uptake in BAT (n = 8) remained unaffected by resveratrol. In vitro experiments in adipocytes derived from human BAT confirmed the lack of effect on BAT. CONCLUSIONS: Resveratrol stimulates muscle mitochondrial function in FDR males, which is in concordance with previous results. However, no other metabolic benefits of resveratrol were found in this group. This could be attributed to subject characteristics causing alterations in metabolism of resveratrol and thereby affecting resveratrol's effectiveness. CLINICALTRIALS. GOV ID: NCT02129595.
Assuntos
Tecido Adiposo Marrom/efeitos dos fármacos , Diabetes Mellitus Tipo 2/prevenção & controle , Hipoglicemiantes/farmacologia , Resistência à Insulina , Mitocôndrias Musculares/efeitos dos fármacos , Resveratrol/farmacologia , Tecido Adiposo Marrom/metabolismo , Idoso , Diabetes Mellitus Tipo 2/genética , Ácidos Graxos/metabolismo , Glucose/metabolismo , Humanos , Masculino , Pessoa de Meia-Idade , Mitocôndrias Musculares/metabolismo , LinhagemRESUMO
Low levels of physical activity and the presence of obesity are associated with mitochondrial dysfunction. In addition, mitochondrial dysfunction has been associated with the development of insulin resistance and type 2 diabetes mellitus (T2DM). Although the evidence for a causal relationship between mitochondrial function and insulin resistance is still weak, emerging evidence indicates that boosting mitochondrial function might be beneficial to patient health. Exercise training is probably the most recognized promoter of mitochondrial function and insulin sensitivity and hence is still regarded as the best strategy to prevent and treat T2DM. Animal data, however, have revealed several new insights into the regulation of mitochondrial metabolism, and novel targets for interventions to boost mitochondrial function have emerged. Importantly, many of these targets seem to be regulated by factors such as nutrition, ambient temperature and circadian rhythms, which provides a basis for nonpharmacological strategies to prevent or treat T2DM in humans. Here, we will review the current evidence that mitochondrial function can be targeted therapeutically to improve insulin sensitivity and to prevent T2DM, focusing mainly on human intervention studies.
Assuntos
Ritmo Circadiano , Diabetes Mellitus Tipo 2/terapia , Dietoterapia , Terapia por Exercício , Resistência à Insulina , Mitocôndrias Musculares/metabolismo , Músculo Esquelético/metabolismo , Temperatura , Restrição Calórica , Carnitina/uso terapêutico , Crioterapia , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/fisiopatologia , Suplementos Nutricionais , Exercício Físico , Humanos , Músculo Esquelético/fisiopatologia , Obesidade/metabolismo , Obesidade/fisiopatologia , SonoRESUMO
BACKGROUND: The obese insulin-resistant state is characterized by impairments in lipid metabolism. We previously showed that 3-d supplementation of combined epigallocatechin-3-gallate and resveratrol (EGCG+RES) increased energy expenditure and improved the capacity to switch from fat toward carbohydrate oxidation with a high-fat mixed meal (HFMM) test in men. OBJECTIVE: The present study aimed to investigate the longer-term effect of EGCG+RES supplementation on metabolic profile, mitochondrial capacity, fat oxidation, lipolysis, and tissue-specific insulin sensitivity. DESIGN: In this randomized double-blind study, 38 overweight and obese subjects [18 men; aged 38 ± 2 y; body mass index (kg/m(2)): 29.7 ± 0.5] received either EGCG+RES (282 and 80 mg/d, respectively) or placebo for 12 wk. Before and after the intervention, oxidative capacity and gene expression were assessed in skeletal muscle. Fasting and postprandial (HFMM) lipid metabolism was assessed by using indirect calorimetry, blood sampling, and microdialysis. Tissue-specific insulin sensitivity was assessed by a hyperinsulinemic-euglycemic clamp with [6,6-(2)H2]-glucose infusion. RESULTS: EGCG+RES supplementation did not affect the fasting plasma metabolic profile. Although whole-body fat mass was not affected, visceral adipose tissue mass tended to decrease after the intervention compared with placebo (P-time × treatment = 0.09). EGCG+RES supplementation significantly increased oxidative capacity in permeabilized muscle fibers (P-time × treatment < 0.05, P-EGCG+RES < 0.05). Moreover, EGCG+RES reduced fasting (P-time × treatment = 0.03) and postprandial respiratory quotient (P-time × treatment = 0.01) compared with placebo. Fasting and postprandial fat oxidation was not significantly affected by EGCG+RES (P-EGCG+RES = 0.46 and 0.38, respectively) but declined after placebo (P-placebo = 0.05 and 0.03, respectively). Energy expenditure was not altered (P-time × treatment = 0.96). Furthermore, EGCG+RES supplementation attenuated the increase in plasma triacylglycerol concentrations during the HFMM test that was observed after placebo (P-time × treatment = 0.04, P-placebo = 0.01). Finally, EGCG+RES had no effect on insulin-stimulated glucose disposal, suppression of endogenous glucose production, or lipolysis. CONCLUSION: Twelve weeks of EGCG+RES supplementation increased mitochondrial capacity and stimulated fat oxidation compared with placebo, but this did not translate into increased tissue-specific insulin sensitivity in overweight and obese subjects. This trial was registered at clinicaltrials.gov as NCT02381145.
Assuntos
Catequina/análogos & derivados , Resistência à Insulina , Metabolismo dos Lipídeos/efeitos dos fármacos , Mitocôndrias/efeitos dos fármacos , Obesidade , Extratos Vegetais/farmacologia , Estilbenos/farmacologia , Adulto , Glicemia/metabolismo , Catequina/farmacologia , Suplementos Nutricionais , Método Duplo-Cego , Metabolismo Energético/efeitos dos fármacos , Jejum , Feminino , Humanos , Insulina/sangue , Gordura Intra-Abdominal/metabolismo , Masculino , Mitocôndrias/metabolismo , Músculos/efeitos dos fármacos , Músculos/metabolismo , Obesidade/metabolismo , Período Pós-Prandial , Resveratrol , Estilbenos/uso terapêuticoRESUMO
Genistein, a natural food compound mainly present in soybeans, is considered a potent antioxidant and to improve glucose homeostasis. However, its mechanism of action remains poorly understood. Here, we analyzed whether genistein could antagonize the progression of the hyperinsulinemic normoglycemic state (pre-diabetes) toward full-blown T2DM in Zucker Diabetic Fatty (ZDF) rats by decreasing mitochondrial oxidative stress and improving skeletal muscle oxidative capacity. Rats were assigned to three groups: (1) lean control (CNTL), (2) fa/fa CNTL, and (3) fa/fa genistein (GEN). GEN animals were subjected to a 0.02% (w/w) genistein-enriched diet for 8 weeks, whereas CNTL rats received a standard diet. We show that genistein did not affect the overall response to a glucose challenge in ZDF rats. In fact, genistein may exacerbate glucose intolerance as fasting glucose levels were significantly higher in fa/fa GEN (17.6 ± 0.7 mM) compared with fa/fa CNTL animals (14.9 ± 1.4 mM). Oxidative stress, established by electron spin resonance (ESR) spectroscopy, carbonylated protein content and UCP3 levels, remained unchanged upon dietary genistein supplementation. Furthermore, respirometry measurements revealed no effects of genistein on mitochondrial function. In conclusion, dietary genistein supplementation did not improve glucose homeostasis, alleviate oxidative stress, or augment skeletal muscle metabolism in ZDF rats.
Assuntos
Dieta , Genisteína/farmacologia , Resistência à Insulina , Músculo Esquelético/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Animais , Glicemia/metabolismo , Peso Corporal/efeitos dos fármacos , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/fisiopatologia , Genisteína/administração & dosagem , Glucose/metabolismo , Teste de Tolerância a Glucose , Homeostase/efeitos dos fármacos , Mitocôndrias Musculares/efeitos dos fármacos , Mitocôndrias Musculares/metabolismo , Músculo Esquelético/metabolismo , Oxirredução/efeitos dos fármacos , Fitoestrógenos/administração & dosagem , Fitoestrógenos/farmacologia , Ratos ZuckerRESUMO
Acylcarnitine metabolites have gained attention as biomarkers of nutrient stress, but their physiological relevance and metabolic purpose remain poorly understood. Short-chain carnitine conjugates, including acetylcarnitine, derive from their corresponding acyl-CoA precursors via the action of carnitine acetyltransferase (CrAT), a bidirectional mitochondrial matrix enzyme. We show here that contractile activity reverses acetylcarnitine flux in muscle, from net production and efflux at rest to net uptake and consumption during exercise. Disruption of this switch in mice with muscle-specific CrAT deficiency resulted in acetyl-CoA deficit, perturbed energy charge, and diminished exercise tolerance, whereas acetylcarnitine supplementation produced opposite outcomes in a CrAT-dependent manner. Likewise, in exercise-trained compared to untrained humans, post-exercise phosphocreatine recovery rates were positively associated with CrAT activity and coincided with dramatic shifts in muscle acetylcarnitine dynamics. These findings show acetylcarnitine serves as a critical acetyl buffer for working muscles and provide insight into potential therapeutic strategies for combatting exercise intolerance.
Assuntos
Acetilcoenzima A/metabolismo , Carnitina O-Acetiltransferase/metabolismo , Carnitina/análogos & derivados , Fadiga Muscular , Músculos/enzimologia , Animais , Carnitina/sangue , Carnitina/metabolismo , Exercício Físico , Humanos , Camundongos Endogâmicos C57BL , Músculos/metabolismo , Condicionamento Físico AnimalRESUMO
Fat accumulation in skeletal muscle combined with low mitochondrial oxidative capacity is associated with insulin resistance (IR). Endurance-trained athletes, characterized by a high oxidative capacity, have elevated intramyocellular lipids, yet are highly insulin sensitive. We tested the hypothesis that a high oxidative capacity could attenuate lipid-induced IR. Nine endurance-trained (age = 23.4 ± 0.9 years; BMI = 21.2 ± 0.6 kg/m(2)) and 10 untrained subjects (age = 21.9 ± 0.9 years; BMI = 22.8 ± 0.6 kg/m(2)) were included and underwent a clamp with either infusion of glycerol or intralipid. Muscle biopsies were taken to perform high-resolution respirometry and protein phosphorylation/expression. Trained subjects had ~32% higher mitochondrial capacity and ~22% higher insulin sensitivity (P < 0.05 for both). Lipid infusion reduced insulin-stimulated glucose uptake by 63% in untrained subjects (P < 0.05), whereas this effect was blunted in trained subjects (29%, P < 0.05). In untrained subjects, lipid infusion reduced oxidative and nonoxidative glucose disposal (NOGD), whereas trained subjects were completely protected against lipid-induced reduction in NOGD, supported by dephosphorylation of glycogen synthase. We conclude that chronic exercise training attenuates lipid-induced IR and specifically attenuates the lipid-induced reduction in NOGD. Signaling data support the notion that high glucose uptake in trained subjects is maintained by shuttling glucose toward storage as glycogen.
Assuntos
Exercício Físico/fisiologia , Resistência à Insulina/fisiologia , Músculo Esquelético/metabolismo , Resistência Física/fisiologia , Emulsões/farmacologia , Emulsões Gordurosas Intravenosas/farmacologia , Humanos , Insulina/metabolismo , Metabolismo dos Lipídeos/efeitos dos fármacos , Metabolismo dos Lipídeos/fisiologia , Masculino , Músculo Esquelético/efeitos dos fármacos , Oxirredução/efeitos dos fármacos , Fosfolipídeos/farmacologia , Fosforilação , Transdução de Sinais/fisiologia , Óleo de Soja/farmacologia , Adulto JovemRESUMO
Insulin resistance is characterized by disturbances in lipid metabolism in skeletal muscle. Our aim was to investigate whether gene expression and fatty acid (FA) profile of skeletal muscle lipids are affected by diets differing in fat quantity and quality in subjects with the metabolic syndrome (MetS) and varying degrees of insulin sensitivity. 84 subjects (age 57.3±0.9 y, BMI 30.9±0.4 kg/m(2), 42 M/42 F) were randomly assigned to one of four iso-energetic diets: high-SFA (HSFA); high-MUFA (HMUFA) or two low-fat, high-complex carbohydrate diets, supplemented with 1.24 g/day of long-chain n-3 PUFA (LFHCCn-3) or control oil (LFHCC) for 12 weeks. In a subgroup of men (n=26), muscle TAG, DAG, FFA and phospholipid contents were determined including their fractional synthetic rate (FSR) and FA composition at fasting and 4h after consumption of a high-fat mixed-meal, both pre- and post-intervention. Genes involved in lipogenesis were downregulated after HMUFA (mean fold change -1.3) and after LFHCCn-3 (fold change -1.7) in insulin resistant subjects (< median of (S(I))), whereas in insulin sensitive subjects (>median of insulin sensitivity) the opposite effect was shown (fold change +1.6 for both diets). HMUFA diet tended to decrease FSR in TAG (P=.055) and DAG (P=.066), whereas the LFHCCn-3 diet reduced TAG content (P=.032). In conclusion, HMUFA and LFHCCn-3 diets reduced the expression of the lipogenic genes in skeletal muscle of insulin resistant subjects, whilst HMUFA reduced the fractional synthesis rate of DAG and TAG and LFHCC n-3 the TAG content. Our data indicate that these diets may reduce muscle fat accumulation by affecting the balance between FA synthesis, storage and oxidation.
Assuntos
Gorduras na Dieta/administração & dosagem , Ácidos Graxos/metabolismo , Síndrome Metabólica/metabolismo , Músculo Esquelético/metabolismo , Sequência de Bases , Primers do DNA , DNA Mitocondrial/metabolismo , Feminino , Expressão Gênica , Humanos , Resistência à Insulina , Lipogênese/genética , Masculino , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase em Tempo RealRESUMO
The natural polyphenolic compound resveratrol was first discovered in the 1940s. In the recent years, this compound received renewed interest as several findings implicated resveratrol as a potent SIRT1 activator capable of mimicking the effects of calorie restriction, and regulating longevity in lower organisms. Given the worldwide increase in age-related metabolic diseases the beneficial effects of resveratrol on metabolism and healthy aging in humans are currently a topic of intense investigation.
Assuntos
Envelhecimento/metabolismo , Restrição Calórica , Metabolismo Energético/efeitos dos fármacos , Ativadores de Enzimas/uso terapêutico , Inibidores de Fosfodiesterase/uso terapêutico , Estilbenos/uso terapêutico , Leveduras/efeitos dos fármacos , Animais , Ativação Enzimática , Ativadores de Enzimas/administração & dosagem , Ativadores de Enzimas/farmacocinética , Medicina Baseada em Evidências , Proteínas Fúngicas/metabolismo , Humanos , Inibidores de Fosfodiesterase/administração & dosagem , Inibidores de Fosfodiesterase/farmacocinética , Resveratrol , Sirtuína 1/metabolismo , Estilbenos/administração & dosagem , Estilbenos/farmacocinética , Leveduras/enzimologiaRESUMO
Resveratrol is a natural compound that affects energy metabolism and mitochondrial function and serves as a calorie restriction mimetic, at least in animal models of obesity. Here, we treated 11 healthy, obese men with placebo and 150 mg/day resveratrol (resVida) in a randomized double-blind crossover study for 30 days. Resveratrol significantly reduced sleeping and resting metabolic rate. In muscle, resveratrol activated AMPK, increased SIRT1 and PGC-1α protein levels, increased citrate synthase activity without change in mitochondrial content, and improved muscle mitochondrial respiration on a fatty acid-derived substrate. Furthermore, resveratrol elevated intramyocellular lipid levels and decreased intrahepatic lipid content, circulating glucose, triglycerides, alanine-aminotransferase, and inflammation markers. Systolic blood pressure dropped and HOMA index improved after resveratrol. In the postprandial state, adipose tissue lipolysis and plasma fatty acid and glycerol decreased. In conclusion, we demonstrate that 30 days of resveratrol supplementation induces metabolic changes in obese humans, mimicking the effects of calorie restriction.
Assuntos
Tecido Adiposo/efeitos dos fármacos , Restrição Calórica/métodos , Fígado/efeitos dos fármacos , Mitocôndrias Musculares/efeitos dos fármacos , Músculo Esquelético/efeitos dos fármacos , Obesidade/tratamento farmacológico , Estilbenos/uso terapêutico , Quinases Proteína-Quinases Ativadas por AMP , Tecido Adiposo/metabolismo , Alanina Transaminase/análise , Glicemia/análise , Pressão Sanguínea , Citrato (si)-Sintase/biossíntese , Estudos Cross-Over , Método Duplo-Cego , Metabolismo Energético/efeitos dos fármacos , Ácidos Graxos/metabolismo , Glicerol/sangue , Proteínas de Choque Térmico/biossíntese , Humanos , Fígado/metabolismo , Masculino , Pessoa de Meia-Idade , Mitocôndrias Musculares/metabolismo , Músculo Esquelético/metabolismo , Países Baixos , Obesidade/metabolismo , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo , Proteínas Quinases/biossíntese , Resveratrol , Sirtuína 1/biossíntese , Estilbenos/administração & dosagem , Suíça , Fatores de Transcrição/biossíntese , Triglicerídeos/sangueRESUMO
Peroxisome proliferator-activated receptors (PPARs) are nuclear hormone receptors that regulate genes involved in energy metabolism and inflammation. For biological activity, PPARs require cognate lipid ligands, heterodimerization with retinoic X receptors, and coactivation by PPAR-γ coactivator-1α or PPAR-γ coactivator-1ß (PGC-1α or PGC-1ß, encoded by Ppargc1a and Ppargc1b, respectively). Here we show that lipolysis of cellular triglycerides by adipose triglyceride lipase (patatin-like phospholipase domain containing protein 2, encoded by Pnpla2; hereafter referred to as Atgl) generates essential mediator(s) involved in the generation of lipid ligands for PPAR activation. Atgl deficiency in mice decreases mRNA levels of PPAR-α and PPAR-δ target genes. In the heart, this leads to decreased PGC-1α and PGC-1ß expression and severely disrupted mitochondrial substrate oxidation and respiration; this is followed by excessive lipid accumulation, cardiac insufficiency and lethal cardiomyopathy. Reconstituting normal PPAR target gene expression by pharmacological treatment of Atgl-deficient mice with PPAR-α agonists completely reverses the mitochondrial defects, restores normal heart function and prevents premature death. These findings reveal a potential treatment for the excessive cardiac lipid accumulation and often-lethal cardiomyopathy in people with neutral lipid storage disease, a disease marked by reduced or absent ATGL activity.
Assuntos
Cardiomiopatias/metabolismo , Ácidos Graxos/metabolismo , Lipase/metabolismo , Mitocôndrias/fisiologia , PPAR alfa/metabolismo , Fatores de Transcrição/metabolismo , Triglicerídeos/metabolismo , Animais , Western Blotting , Cardiomiopatias/etiologia , Primers do DNA/genética , DNA Complementar/genética , DNA Mitocondrial/genética , Ecocardiografia , Dosagem de Genes , Lipase/genética , Luciferases , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Microscopia Eletrônica de Transmissão , Miócitos Cardíacos/fisiologia , Oxirredução , Consumo de Oxigênio/fisiologia , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Sarcolema/fisiologiaRESUMO
Skeletal muscle triglyceride accumulation is associated with insulin resistance in obesity. Recently, it has been suggested that alpha lipoic acid (ALA) improves insulin sensitivity by lowering triglyceride accumulation in nonadipose tissues via activation of skeletal muscle AMP-activated protein kinase (AMPK). We examined whether chronic ALA supplementation prevents muscular lipid accumulation that is associated with high-fat diets via activation of AMPK. In addition, we tested if ALA supplementation was able to improve insulin sensitivity in rats fed low- and high-fat diets (LFD, HFD). Supplementing male Wistar rats with 0.5% ALA for 8 weeks significantly reduced body weight, both on LFD and HFD (-24% LFD+ALA vs. LFD, P < 0.01, and -29% HFD+ALA vs. HFD, P < 0.001). Oil red O lipid staining revealed a 3-fold higher lipid content in skeletal muscle after HFD compared with LFD and ALA-supplemented groups (P < 0.05). ALA improved whole body glucose tolerance ( approximately 20% lower total area under the curve (AUC) in ALA supplemented groups vs. controls, P < 0.05). These effects were not mediated by increased muscular AMPK activation or ALA-induced improvement of muscular insulin sensitivity. To conclude, the prevention of HFD-induced muscular lipid accumulation and the improved whole body glucose tolerance are likely secondary effects due to the anorexic nature of ALA.