Training at low intensities with moderate vascular occlusion results in increased muscle hypertrophy, strength, and endurance. Elastic knee wraps, applied to the proximal portion of the target muscle, might elicit a stimulus similar to the KAATSU Master Apparatus. The purpose of this study was to test the hypothesis that intermittently occluding the leg extensors with elastic knee wraps would increase whole-blood lactate (WBL) over control (CON). Twelve healthy men and women participated in this study (age 21.2 ± 0.35 years, height 168.9 ± 2.60 cm, and body mass 71.2 ± 4.16 kg). One repetition maximum (1RM) testing for the leg extensors was performed on a leg extension machine for the first trial, followed by occlusion (OCC) and CON trials. Four sets of leg extension exercise (30-15-15-15) were completed with 150-second rest between sets at 30% 1RM. Whole-blood lactate, heart rate (HR), and ratings of perceived exertion (RPEs) were measured after every set of exercise and 3 minutes postexercise. Data were analyzed using repeated-measures analysis of variance with statistical significance set at p ≤ 0.05. Whole-blood lactate increased in response to exercise (p = 0.01) but was not different between groups (OCC 6.28 ± 0.66 vs. CON 5.35 ± 0.36 mmol·L, p = 0.051). Heart rate (OCC 128.86 ± 4.37 vs. CON 119.72 ± 4.10 b·min⁻¹) was higher with OCC from sets 2-4 (p ≤ 0.03), with no difference 3 minutes postexercise (p = 0.29). Rating of perceived exertion was higher with OCC after every set (OCC 15.10 ± 0.31 vs. CON 12.16 ± 0.50, p = 0.01). In conclusion, no differences exist for WBL between groups, although there was a trend for higher levels with OCC. The current protocol for practical occlusion did not significantly increase metabolic stress more than normal low-intensity exercise. This study does not support the use of knee wraps as a mode of blood-flow restriction.

Hepatic mitochondrial adaptations to exercise are largely unknown. PURPOSE Here we sought to determine the effects of various exercise modalities on measures of hepatic mitochondrial function and metabolism. METHODS Male Sprague Dawley rats were randomly assigned (n=8-10 per group) into sedentary (SED), voluntary wheel running (VWR), VWR with food pulled during the dark cycle (VMR-OF), treadmill endurance exercise (TM-END; 30 m/min, 12% gradient, 60 min/d, 5 d/wk), or treadmill interval sprint training (TM-IST; 50 m/min, 12% gradient, 6×2.5 min bouts, 5 d/wk) groups for a 4 week intervention. RESULTS Hepatic mitochondrial state 3 and maximal uncoupled respiration were significantly (p<0.05) increased in all 4 exercise groups compared with SED animals. In addition, hepatic mitochondrial [1-14C] pyruvate oxidation to CO2, an index of pyruvate dehydrogenase (PDH) activity was significantly increased in VWR-OF, TM-END, and TM-IST rats (p<0.05); whereas, exercise-induced increases in [2-14C] pyruvate oxidation and [1-14C] palmitate oxidation to CO2 did not reach statistical significance. Hepatic mitochondrial sirtuin 3 (SIRT3) protein content, which putatively increases activity of mitochondrial proteins, was elevated in the VWR, VWR-OF and TM-END groups (p<0.05). Additionally, only VWR-OF animals experienced increases in hepatic cytochrome c protein content and PEPCK mRNA, while PGC-1α mRNA expression and phospho-CREB protein content was increased in VWR-OF and TM-END groups. CONCLUSION Four weeks of exercise training, regardless of exercise modality, significantly increased hepatic mitochondrial respiration and evoked other unique improvements in mitochondrial metabolism that do not appear to be dependent on increases in mitochondrial content.

Thyfault JP, Rector RS. Combining metformin and aerobic exercise training in the treatment of type 2 diabetes and NAFLD in OLETF rats. Am J Physiol Endocrinol Metab 306: E300 -E310, 2014. First published December 10, 2013; doi:10.1152/ajpendo.00427.2013.-Here, we sought to compare the efficacy of combining exercise and metformin for the treatment of type 2 diabetes and nonalcoholic fatty liver disease (NAFLD) in hyperphagic, obese, type 2 diabetic Otsuka Long-Evans Tokushima Fatty (OLETF) rats. OLETF rats (age: 20 wk, hyperglycemic and hyperinsulinemic; n ϭ 10/group) were randomly assigned to sedentary (O-SED), SED plus metformin (O-SED ϩ M; 300 mg·kg Ϫ1 ·day Ϫ1 ), moderate-intensity exercise training (O-EndEx; 20 m/min, 60 min/day, 5 days/wk treadmill running), or O-EndEx ϩ M groups for 12 wk. Long-Evans Tokushima Otsuka (L-SED) rats served as nonhyperphagic controls. O-SED ϩ M, O-EndEx, and O-EndEx ϩ M were effective in the management of type 2 diabetes, and all three treatments lowered hepatic steatosis and serum markers of liver injury; however, O-EndEx lowered liver triglyceride content and fasting hyperglycemia more than O-SED ϩ M. In addition, exercise elicited greater improvements compared with metformin alone on postchallenge glycemic control, liver diacylglycerol content, hepatic mitochondrial palmitate oxidation, citrate synthase, and ␤-HAD activities and in the attenuation of markers of hepatic fatty acid uptake and de novo fatty acid synthesis. Surprisingly, combining metformin and aerobic exercise training offered little added benefit to these outcomes, and in fact, metformin actually blunted exerciseinduced increases in complete mitochondrial palmitate oxidation and ␤-HAD activity. In conclusion, aerobic exercise training was more effective than metformin administration in the management of type 2 diabetes and NAFLD outcomes in obese hyperphagic OLETF rats. Combining therapies offered little additional benefit beyond exercise alone, and findings suggest that metformin potentially impairs exercise-induced hepatic mitochondrial adaptations. exercise training; metformin; nonalcoholic fatty liver disease; hepatic mitochondria; de novo lipogenesis; Otsuka Long-Evans Tokushima Fatty rats NONALCOHOLIC FATTY LIVER DISEASE (NAFLD) is a progressive liver disease characterized by hepatic triglyceride (TG) accumulation (Ն5% by weight for diagnosis) that occurs in the absence of excess alcohol consumption (Ͼ20 g/day). It encompasses a histological spectrum ranging from simple hepatic steatosis to nonalcoholic steatohepatitis, advanced fibrosis, and cirrhosis (40). NAFLD is considered the hepatic manifestation of the metabolic syndrome (11), and it affects ϳ30% of the US adult population (3, 7) and ϳ70% of type 2 diabetics (52). However, there are currently no clear guidelines for the treatment of NAFLD.A component of prevention and treatment recommendations addressing NAFLD involves lifestyle modifications that alter net energy status. Indeed, both short-term (6) and longer-term caloric restriction (10, 23), a...

PURPOSE Elevated postprandial glycemic excursions (PPG) are significant risk factors for cardiovascular disease in type 2 diabetes patients. Here we tested if and for how many meals a single bout of exercise would reduce PPG responses to subsequent meals in type 2 diabetes (T2D) patients using continuous glucose monitors (CGMS). METHODS We recruited 9 sedentary (<30 minutes/week of exercise) individuals with T2D (BMI: 36.0 ± 1.1 kg/m2; age 60.3 ± 1.0 years; HbA1c: 6.3 ± 0.2 %). The subjects consumed a eucaloric diet (51% carbohydrate, 31% fat, 18% protein) consisting of 3 meals, identical in composition, over a 2-day period while wearing CGMS in two different conditions (exercise (EX; one 60 minute bout at 60-75% of heart rate reserve performed prior to breakfast) vs. a sedentary (SED) condition). We quantified 24-h average glucose, PPG-AUC (4 h glucose AUC following meals) and PPG-2 h (2 hour post-prandial glucose). RESULTS EX significantly reduced average [glucose] during the first 24 hour period (p=0.03). EX caused a reduction in PPG-AUC (p=0.02) for all of the meals over the two days (main effect between conditions). Comparison between the EX and SED conditions at each meal revealed that EX reduced PPG-AUC following the second meal of day 1 (lunch) (p=0.04). PPG-2 h was not significantly different between EX and SED. CONCLUSION Although a single EX bout does lower 24-h average [glucose], it only significantly lowered PPG-AUC at the second meal following the bout suggesting that daily exercise may be needed to most effectively improve PPG at the advent of exercise training in T2D patients.

PS, Thyfault JP. Intrinsic aerobic capacity impacts susceptibility to acute high-fat diet-induced hepatic steatosis. Am J Physiol Endocrinol Metab 307: E355-E364, 2014. First published June 24, 2014; doi:10.1152/ajpendo.00093.2014.-Aerobic capacity/fitness significantly impacts susceptibility for fatty liver and diabetes, but the mechanisms remain unknown. Herein, we utilized rats selectively bred for high (HCR) and low (LCR) intrinsic aerobic capacity to examine the mechanisms by which aerobic capacity impacts metabolic vulnerability for fatty liver following a 3-day high-fat diet (HFD). Indirect calorimetry assessment of energy metabolism combined with radiolabeled dietary food was employed to examine systemic metabolism in combination with ex vivo measurements of hepatic lipid oxidation. The LCR, but not HCR, displayed increased hepatic lipid accumulation in response to the HFD despite both groups increasing energy intake. However, LCR rats had a greater increase in energy intake and demonstrated greater daily weight gain and percent body fat due to HFD compared with HCR. Additionally, total energy expenditure was higher in the larger LCR. However, controlling for the difference in body weight, the LCR has lower resting energy expenditure compared with HCR. Importantly, respiratory quotient was significantly higher during the HFD in the LCR compared with HCR, suggesting reduced whole body lipid utilization in the LCR. This was confirmed by the observed lower whole body dietary fatty acid oxidation in LCR compared with HCR. Furthermore, LCR liver homogenate and isolated mitochondria showed lower complete fatty acid oxidation compared with HCR. We conclude that rats bred for low intrinsic aerobic capacity show greater susceptibility for dietary-induced hepatic steatosis, which is associated with a lower energy expenditure and reduced whole body and hepatic mitochondrial lipid oxidation. fatty liver; energy intake; fitness; obesity; energy expenditure LOW AEROBIC CAPACITY OR FITNESS is a powerful predictor of cardiovascular and all-cause mortality independent of other risk factors, including smoking, obesity, previous cardiovascular disease, and diabetes (18,19). Importantly, improving fitness also significantly increases survival in previously low-fit individuals (19). Aerobic capacity is also an independent predictor for the development of the metabolic syndrome and type 2 diabetes (12, 34). Low aerobic capacity is also a powerful predictor of nonalcoholic fatty liver disease (NA-FLD) prevalence (2) and negatively impacts lifestyle-based treatments for NAFLD (16). However, the mechanism(s) linking low aerobic capacity to metabolic disease processes remains unknown. In particular, there are limited data documenting the whole body and liver-specific energy metabolism phenotypes that exist between groups of differing aerobic capacities and how these different phenotypes may modulate susceptibility for NAFLD.NAFLD represents a spectrum of disease initially characterized by steatosis that may progress to hepatic in...

BACKGROUND. Insulin is a key regulator of metabolic function. The effects of excess adiposity, insulin resistance, and hepatic steatosis on the complex integration of insulin secretion and hepatic and extrahepatic tissue extraction are not clear. METHODS.A hyperinsulinemic-euglycemic clamp and a 3-hour oral glucose tolerance test were performed to evaluate insulin sensitivity and insulin kinetics after glucose ingestion in 3 groups: (a) lean subjects with normal intrahepatic triglyceride (IHTG) and glucose tolerance (lean-NL; n = 14), (b) obese subjects with normal IHTG and glucose tolerance (obese-NL; n = 24), and (c) obese subjects with nonalcoholic fatty liver disease (NAFLD) and prediabetes (obese-NAFLD; n = 22). RESULTS.Insulin sensitivity progressively decreased and insulin secretion progressively increased from the lean-NL to the obese-NL to the obese-NAFLD groups. Fractional hepatic insulin extraction progressively decreased from the lean-NL to the obese-NL to the obese-NAFLD groups, whereas total hepatic insulin extraction (molar amount removed) was greater in the obese-NL and obese-NAFLD subjects than in the lean-NL subjects. Insulin appearance in the systemic circulation and extrahepatic insulin extraction progressively increased from the lean-NL to the obese-NL to the obese-NAFLD groups. Total hepatic insulin extraction plateaued at high rates of insulin delivery, whereas the relationship between systemic insulin appearance and total extrahepatic extraction was linear. CONCLUSION.Hyperinsulinemia after glucose ingestion in obese-NL and obese-NAFLD is due to an increase in insulin secretion, without a decrease in total hepatic or extrahepatic insulin extraction. However, the liver's maximum capacity to remove insulin is limited because of a saturable extraction process. The increase in insulin delivery to the liver and extrahepatic tissues in obese-NAFLD is unable to compensate for the increase in insulin resistance, resulting in impaired glucose homeostasis. TRIAL REGISTRATION. ClinicalTrials.gov NCT02706262.

Objective The role of metabolic condition and diet in regulating circulating levels of adropin, a peptide hormone linked to cardiometabolic control, is not well understood. Here we examined weight loss and diet effects on plasma adropin concentrations. Methods The present report includes data from (1) a weight loss trial, (2) an evaluation of acute exercise effects on mixed-meal tolerance test responses, and (3) a meta-analysis to determine normal fasting adropin concentrations. Results Plasma adropin concentrations exhibit a distribution with positive skew and kurtosis. The effect of weight loss on plasma adropin concentrations was dependent on baseline plasma adropin concentrations, with an inverse association between baseline and a decline in concentrations after weight loss (Spearman’s ρ=−0.575; P<0.001). When ranked by baseline plasma adropin concentrations, only values in the upper quartile declined with weight loss. Plasma adropin concentrations under the bell-curve correlated negatively with habitual carbohydrate intake and plasma lipids. There was a negative correlation between baseline values and a transient decline in plasma adropin during the MMTT Conclusions Plasma adropin concentrations in humans are sensitive to dietary macronutrients, perhaps due to habitual consumption of carbohydrate-rich diets suppressing circulating levels. Very high adropin levels may indicate cardiometabolic conditions sensitive to weight loss.

Purpose The incretin hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) help regulate postprandial triacylglycerol (TAG) and insulin concentrations, but the effects of acute aerobic exercise on GLP-1 or GIP responses are unclear. The purpose of this study was to determine if reductions in postprandial TAG and insulin with exercise are associated with GLP-1 and GIP responses. Methods Thirteen normal-weight (NW) and 13 Obese (Ob) individuals participated in two, 4-d trials in random order including an exercise (EX) and a no exercise (NoEX) trial. Diet was controlled during both trials. The EX trial consisted of 1 h of treadmill walking (55–60% of VO2peak) during the evening of day 3 of the trial, 12 h prior to a 4 h mixed meal test on day 4, during which frequent blood samples were taken to assess postprandial lipemia, glycemia, insulin, c-peptide, GIP, and GLP-1 responses. Insulin secretion was estimated using the Insulinogenic Index and insulin clearance was estimated using the ratio of insulin to c-peptide. Results Postprandial TAG’s were 29% lower after EX in Ob individuals (P<0.05) but were not significantly altered in NW individuals (P>0.05). The drop in postprandial high-density lipoprotein cholesterol was attenuated with EX in Ob individuals (P<0.05). Insulin responses were 14% lower after EX in Ob individuals (P<0.05), and this was associated with reduced insulin secretion (P<0.05), with no change in insulin clearance (P>0.05). Glucose, c-peptide, GIP, and GLP-1 were not different between trials. Conclusion A 1 h bout of moderate intensity aerobic exercise the night prior to a mixed meal attenuates TAG and insulin responses in Ob, but not NW, individuals, an effect not associated with altered GLP-1 or GIP responses.