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Human obesity is characterized by defective fat storage and enhanced muscle fatty acid oxidation, and trimetazidine gradually counteracts these abnormalities.
Bucci, M, Borra, R, Någren, K, Maggio, R, Tuunanen, H, Oikonen, V, Del Ry, S, Viljanen, T, Taittonen, M, Rigazio, S, et al
American journal of physiology. Endocrinology and metabolism. 2011;(1):E105-12
Abstract
An impaired ability to store fatty acids (FA) in subcutaneous adipose tissue (SAT) may be implicated in the pathogenesis of obesity-related diseases via overexposure of lean tissues and production of free radicals from FA oxidation (FAO). We studied regional FA metabolism in skeletal muscle and adipose tissue in humans and investigated the long-term effects of the FAO inhibitor trimetazidine on glucose and FA metabolism. Positron emission tomography (PET) and [(11)C]palmitate were used to compare FA metabolism in SAT and skeletal muscle between eight obese and eight nonobese subjects (BMI ≥/< 30 kg/m(2)). A subgroup of nine subjects underwent a 1-mo trimetazidine administration. PET with [(11)C]palmitate and [(18)F]fluorodeoxyglucose, indirect calorimetry, and MRI before and after this period were performed to characterize glucose and FA metabolism, fat masses, skeletal muscle triglyceride, and creatine contents. Obesity was characterized by a 100% elevation in FAO and a defect in the FA esterification rate constant (P < 0.05) in skeletal muscle. FA esterification was reduced by ~70% in SAT (P < 0.001) in obese vs. control subjects. The degrees of obesity and insulin resistance were both negatively associated with esterification-related parameters and positively with FAO (P < 0.05). Trimetazidine increased skeletal muscle FA esterification (P < 0.01) and mildly upregulated glucose phosphorylation (P = 0.066). Our data suggest that human obesity is characterized by a defect in tissue FA storage capability, which is accompanied by a (potentially compensatory) elevation in skeletal muscle FAO; trimetazidine diverted FA from oxidative to nonoxidative pathways and provoked an initial activation of glucose metabolism in skeletal muscle.
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Restoration of muscle mitochondrial function and metabolic flexibility in type 2 diabetes by exercise training is paralleled by increased myocellular fat storage and improved insulin sensitivity.
Meex, RC, Schrauwen-Hinderling, VB, Moonen-Kornips, E, Schaart, G, Mensink, M, Phielix, E, van de Weijer, T, Sels, JP, Schrauwen, P, Hesselink, MK
Diabetes. 2010;(3):572-9
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Abstract
OBJECTIVE Mitochondrial dysfunction and fat accumulation in skeletal muscle (increased intramyocellular lipid [IMCL]) have been linked to development of type 2 diabetes. We examined whether exercise training could restore mitochondrial function and insulin sensitivity in patients with type 2 diabetes. RESEARCH DESIGN AND METHODS Eighteen male type 2 diabetic and 20 healthy male control subjects of comparable body weight, BMI, age, and VO2max participated in a 12-week combined progressive training program (three times per week and 45 min per session). In vivo mitochondrial function (assessed via magnetic resonance spectroscopy), insulin sensitivity (clamp), metabolic flexibility (indirect calorimetry), and IMCL content (histochemically) were measured before and after training. RESULTS Mitochondrial function was lower in type 2 diabetic compared with control subjects (P = 0.03), improved by training in control subjects (28% increase; P = 0.02), and restored to control values in type 2 diabetic subjects (48% increase; P < 0.01). Insulin sensitivity tended to improve in control subjects (delta Rd 8% increase; P = 0.08) and improved significantly in type 2 diabetic subjects (delta Rd 63% increase; P < 0.01). Suppression of insulin-stimulated endogenous glucose production improved in both groups (-64%; P < 0.01 in control subjects and -52% in diabetic subjects; P < 0.01). After training, metabolic flexibility in type 2 diabetic subjects was restored (delta respiratory exchange ratio 63% increase; P = 0.01) but was unchanged in control subjects (delta respiratory exchange ratio 7% increase; P = 0.22). Starting with comparable pretraining IMCL levels, training tended to increase IMCL content in type 2 diabetic subjects (27% increase; P = 0.10), especially in type 2 muscle fibers. CONCLUSIONS Exercise training restored in vivo mitochondrial function in type 2 diabetic subjects. Insulin-mediated glucose disposal and metabolic flexibility improved in type 2 diabetic subjects in the face of near-significantly increased IMCL content. This indicates that increased capacity to store IMCL and restoration of improved mitochondrial function contribute to improved muscle insulin sensitivity.
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Coimmunoprecipitation of FAT/CD36 and CPT I in skeletal muscle increases proportionally with fat oxidation after endurance exercise training.
Schenk, S, Horowitz, JF
American journal of physiology. Endocrinology and metabolism. 2006;(2):E254-60
Abstract
Although the increase in fatty acid oxidation after endurance exercise training has been linked with improvements in insulin sensitivity and overall metabolic health, the mechanisms responsible for increasing fatty acid oxidation after exercise training are not completely understood. The primary aim of this study was to determine the effect of adding endurance exercise training to a weight loss program on fat oxidation and the colocalization of the fatty acid translocase FAT/CD36 with carnitine palmitoyltransferase I (CPT I) in human skeletal muscle. We measured postabsorptive fat oxidation and acquired a muscle sample from abdominally obese women before and after 12% body weight loss through either dietary intervention with endurance exercise training (EX + DIET) or dietary intervention without endurance exercise training (DIET). Immunoprecipitation techniques were used on these muscle samples to determine whether the association between FAT/CD36 and CPT I is altered after DIET and/or EX + DIET. FAT/CD36 was found to coimmunoprecipitate with CPT I, and the amount of FAT/CD36 that coimmunoprecipitated with CPT I increased by approximately 25% after EX + DIET (P < 0.005) but was unchanged after DIET. In addition, the increase in the amount of FAT/CD36 that coimmunoprecipitated with CPT I in EX + DIET was strongly correlated with the increase in whole body fat oxidation (R2 = 0.857, P < 0.003). In conclusion, the findings from this study indicate that exercise training alters the localization of FAT/CD36 and increases its association with CPT I, which may help augment fat oxidation.
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Higher skeletal muscle alpha2AMPK activation and lower energy charge and fat oxidation in men than in women during submaximal exercise.
Roepstorff, C, Thiele, M, Hillig, T, Pilegaard, H, Richter, EA, Wojtaszewski, JF, Kiens, B
The Journal of physiology. 2006;(Pt 1):125-38
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Abstract
5'AMP-activated protein kinase (AMPK) is an energy sensor activated by perturbed cellular energy status such as during muscle contraction. Activated AMPK is thought to regulate several key metabolic pathways. We used sex comparison to investigate whether AMPK signalling in skeletal muscle regulates fat oxidation during exercise. Moderately trained women and men completed 90 min bicycle exercise at 60% VO2peak. Both AMPK Thr172 phosphorylation and alpha2AMPK activity were increased by exercise in men (approximately 200%, P < 0.001) but not significantly in women. The sex difference in muscle AMPK activation with exercise was accompanied by an increase in muscle free AMP (approximately 164%, P < 0.01), free AMP/ATP ratio (159%, P < 0.05), and creatine (approximately 42%, P < 0.001) in men but not in women (NS), suggesting that lack of AMPK activation in women was due to better maintenance of muscle cellular energy balance compared with men. During exercise, fat oxidation per kg lean body mass was higher in women than in men (P < 0.05). Regression analysis revealed that a higher proportion of type 1 muscle fibres (approximately 23%, P < 0.01) and a higher capillarization (approximately 23%, P < 0.05) in women than in men could partly explain the sex difference in alpha2AMPK activity (r = -0.54, P < 0.05) and fat oxidation (r = 0.64, P < 0.05) during exercise. On the other hand, fat oxidation appeared not to be regulated via AMPK. In conclusion, during prolonged submaximal exercise at 60% VO2peak, higher fat oxidation in women cannot be explained by higher AMPK signalling but is accompanied by improved muscle cellular energy balance in women probably due to sex specific muscle morphology.
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Abnormal intracellular lipid processing contributes to fat malabsorption in cystic fibrosis patients.
Peretti, N, Roy, CC, Drouin, E, Seidman, E, Brochu, P, Casimir, G, Levy, E
American journal of physiology. Gastrointestinal and liver physiology. 2006;(4):G609-15
Abstract
A common feature of cystic fibrosis (CF) is the functional derangement of the exocrine pancreas, which affects output of pancreatic lipase. This condition results in severe dietary malabsorption due to the poor hydrolysis of triacylglycerol (TG) in the lumen of the small intestine. Despite the benefits of pancreatic enzyme supplements, patients with CF present with persistent intestinal fat malabsorption. The aim of the present investigation was to determine whether defects in the intracellular phase of lipid transport occur in this pathophysiology in addition to the known disturbed digestive processes. Our hypothesis was tested by incubating intestinal biopsies from six CF and six healthy subjects with radiolabeled lipid and protein precursors. Lipid esterification and secretion were markedly decreased by 22-31% and 38-42%, respectively, in CF samples, as noted by the low incorporation of [(14)C]palmitic acid into TGs, phospholipids, and cholesteryl esters in patients' duodenal explants and culture media compared with controls (100%). Accordingly, the output of TG-rich lipoproteins was substantially reduced (P < 0.05), and a similar trend was observed for high-density lipoproteins. Because intestinal lipoprotein assembly/secretion shows an absolute requirement for apolipoprotein (apo) B-48, radioactive labeling experiments were performed; these experiments demonstrated a significantly (P < 0.05) diminished synthesis of apoB-48 (40%) and apoA-I (30%). Given the critical role of microsomal triglyceride transfer protein in the formation of apoB-containing lipoproteins, its activity was determined and not found to be altered in CF intestinal tissue. Together, these results suggest that CF malabsorption may also be caused by defects in mucosal mechanisms leading to abnormal lipoprotein delivery into the blood circulation.
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Elevated n-3 fatty acids in a high-fat diet attenuate the increase in PDH kinase activity but not PDH activity in human skeletal muscle.
Turvey, EA, Heigenhauser, GJ, Parolin, M, Peters, SJ
Journal of applied physiology (Bethesda, Md. : 1985). 2005;(1):350-5
Abstract
We tested the hypothesis that a high-fat diet (75% fat; 5% carbohydrates; 20% protein), for which 15% of the fat content was substituted with n-3 fatty acids, would not exhibit the diet-induced increase in pyruvate dehydrogenase kinase (PDK) activity, which is normally observed in human skeletal muscle. The fat content was the same in both the regular high-fat diet (HF) and in the n-3-substituted diet (N3). PDK activity increased after both high-fat diets, but the increase was attenuated after the N3 diet (0.051 +/- 0.007 and 0.218 +/- 0.047 min(-1) for pre- and post-HF, respectively; vs. 0.073 +/- 0.016 and 0.133 +/- 0.032 min(-1) for pre- and post-N3, respectively). However, the active form of pyruvate dehydrogenase (PDHa) activity decreased to a similar extent in both conditions (0.93 +/- 0.17 and 0.43 +/- 0.09 mmol/kg wet wt pre- and post-HF; vs. 0.87 +/- 0.19 and 0.39 +/- 0.05 mmol/kg wet wt pre- and post-N3, respectively). This suggested that the difference in PDK activity did not affect PDHa activation in the basal state, and it was regulated by intramitochondrial effectors, primarily muscle pyruvate concentration. Muscle glycogen content was consistent throughout the study, before and after both diet conditions, whereas muscle glucose-6-phosphate, glycerol-3-phosphate, lactate, and pyruvate were decreased after the high-fat diets. Plasma triglycerides decreased after both high-fat diets but decreased to a greater extent after the N3, whereas plasma free fatty acids increased after both diets, but to a lesser extent after the N3. In summary, PDK activity is decreased after a high-fat diet that is rich in n-3 fatty acids, although PDHa activity was unaltered. In addition, our data demonstrated that the hypolipidemic effect of n-3 fatty acids occurs earlier (3 days) than previously reported and is evident even when the diet has 75% of its total energy derived from fat.
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Effect of carbohydrate ingestion during exercise on post-exercise substrate oxidation and energy intake.
Melby, CL, Osterberg, KL, Resch, A, Davy, B, Johnson, S, Davy, K
International journal of sport nutrition and exercise metabolism. 2002;(3):294-309
Abstract
Thirteen physically active, eumenorrheic, normal-weight (BMI < 25 kg/m2) females, aged 18-30 years, completed 4 experimental conditions, with the order based on a Latin Square Design: (a). CHO/Ex: moderate-intensity exercise (65% VO2peak) with a net energy cost of approximately 500 kcals, during which time the subject consumed a carbohydrate beverage (45 g CHO) at specific time intervals; (b). CHO/NoEx: a period of time identical to (a). but with subjects consuming the carbohydrate while sitting quietly rather than exercising; (c). NoCHO/Ex: same exercise protocol as condition (a.) during which time subjects consumed a non-caloric placebo beverage; and (d). NoCHO/NoEx: same as the no-exercise condition (b). but with subjects consuming a non-caloric placebo beverage. Energy expenditure, and fat and carbohydrate oxidation rates for the entire exercise/sitting period plus a 90-min recovery period were determined by continuous indirect calorimetry. Following recovery, subjects ate ad libitum amounts of food from a buffet and were asked to record dietary intake during the remainder of the day. Total fat oxidation (exercise plus recovery) was attenuated by carbohydrate compared to placebo ingestion by only approximately 4.5 g. There was a trend (p =.08) for a carbohydrate effect on buffet energy intake such that the CHO/Ex and CHO/NoEx energy intakes were lower than the NoCHO/Ex and NoCHO/NoEx energy intakes, respectively (mean for CHO conditions: 683 kcal; NoCHO conditions: 777 kcal). Average total energy intake (buffet plus remainder of the day) was significantly lower (p <.05) following the conditions when carbohydrate was consumed (CHO/Ex = 1470 kcal; CHO/NoEx = 1285 kcal) compared to the noncaloric placebo (NoCHO/Ex =1767 kcal; NoCHO/NoEx = 1660 kcal). In conclusion, in young women engaging in regular exercise, ingestion of 45 g of carbohydrate during exercise only modestly suppresses total fat oxidation during exercise. Furthermore, the ingestion of carbohydrate with or without exercise resulted in a lower energy intake for the remainder of the day.