The circulating level of brain-derived neurotrophic factor (BDNF) is reduced in patients with major depression and type-2 diabetes. Because acute exercise increases BDNF production in the hippocampus and cerebral cortex, we hypothesized that endurance training would enhance the release of BDNF from the human brain as detected from arterial and internal jugular venous blood samples. In a randomized controlled study, 12 healthy sedentary males carried out 3 mo of endurance training ( n = 7) or served as controls ( n = 5). Before and after the intervention, blood samples were obtained at rest and during exercise. At baseline, the training group (58 ± 106 ng·100 g⁻¹·min⁻¹, means ± SD) and the control group (12 ± 17 ng·100 g⁻¹·min⁻¹) had a similar release of BDNF from the brain at rest. Three months of endurance training enhanced the resting release of BDNF to 206 ± 108 ng·100 g⁻¹·min⁻¹ ( P < 0.05), with no significant change in the control subjects, but there was no training-induced increase in the release of BDNF during exercise. Additionally, eight mice completed a 5-wk treadmill running training protocol that increased the BDNF mRNA expression in the hippocampus (4.5 ± 1.6 vs. 1.4 ± 1.1 mRNA/ssDNA; P < 0.05), but not in the cerebral cortex (4.0 ± 1.4 vs. 4.6 ± 1.4 mRNA/ssDNA) compared with untrained mice. The increased BDNF expression in the hippocampus and the enhanced release of BDNF from the human brain following training suggest that endurance training promotes brain health.

Obesity is associated with low-grade inflammation, insulin resistance, type 2 diabetes, and cardiovascular disease. This study investigated the effect of a 15-wk lifestyle intervention (hypocaloric diet and daily exercise) on inflammatory markers in plasma, adipose tissue (AT), and skeletal muscle (SM) in 27 severely obese subjects (mean body mass index: 45.8 kg/m²). Plasma samples, subcutaneous abdominal AT biopsies, and vastus lateralis SM biopsies were obtained before and after the intervention and analyzed by ELISA and RT-PCR. The intervention reduced body weight ( P < 0.001) and increased insulin sensitivity (homeostasis model assessment; P < 0.05). Plasma adiponectin ( P < 0.001) increased, and C-reactive protein ( P < 0.05), IL-6 ( P < 0.01), IL-8 ( P < 0.05), and monocyte chemoattractant protein-1 ( P < 0.01) decreased. AT inflammation was reduced, determined from an increased mRNA expression of adiponectin ( P < 0.001) and a decreased expression of macrophage-specific markers (CD14, CD68), IL-6, IL-8, and tumor necrosis factor-α ( P < 0.01). After adjusting for macrophage infiltration in AT, only IL-6 mRNA was decreased ( P < 0.05). Only very low levels of inflammatory markers were found in SM. The intervention had no effect on adiponectin receptor 1 and 2 mRNA in AT or SM. Thus hypocaloric diet and increased physical activity improved insulin sensitivity and reduced low-grade inflammation. Markers of inflammation were particularly reduced in AT, whereas SM does not contribute to this attenuation of whole body inflammation.

Substrate utilization across the leg during 90 min of bicycle exercise at 58% of peak oxygen uptake (V˙o_2 peak) was studied in seven endurance-trained males and seven endurance-trained, eumenorrheic females by applying arteriovenous catheterization, stable isotopes, and muscle biopsies. The female and male groups were matched according toV˙o_2 peakper kilogram of lean body mass, physical activity level, and training history of the subjects. All subjects consumed the same diet, well controlled in terms of nutrient composition as well as energy content, for 8 days preceding the experiment, and all females were tested in the midfollicular phase of the menstrual cycle. During exercise, respiratory exchange ratio (RER) and leg respiratory quotient (RQ) were similar in females and males. Myocellular triacylglycerol (TG) degradation was negligible in males but amounted to 12.4 ± 3.2 mmol/kg dry wt in females and corresponded to 25.0 ± 6.0 and 5.0 ± 7.3% of total oxygen uptake in females and males, respectively ( P < 0.05). Utilization of plasma fatty acids (12.0 ± 2.5 and 9.6 ± 1.5%), blood glucose (13.6 ± 1.5 and 14.3 ± 1.5%), and glycogen (48.5 ± 4.9 and 42.8 ± 2.1%) were similar in females and males. Thus, in females, measured substrate oxidation accounted for 99% of the leg oxygen uptake, whereas in males 28% of leg oxygen uptake was unaccounted for in terms of measured oxidized lipid substrates. These findings may indicate that males utilized additional lipid sources, presumably very low density lipoprotein-TG or TG located between muscle fibers. On the basis of RER and leg RQ, it is concluded that no gender difference existed in the relative contribution from carbohydrate and lipids to the oxidative metabolism across the leg during submaximal exercise at the same relative workload. However, an effect of gender appears to occur in the utilization of the different lipid sources.

Insulin resistance is currently a major health problem. This may be because of a marked decrease in daily physical activity during recent decades combined with constant food abundance. This lifestyle collides with our genome, which was most likely selected in the late Paleolithic era (50,000–10,000 BC) by criteria that favored survival in an environment characterized by fluctuations between periods of feast and famine. The theory of thrifty genes states that these fluctuations are required for optimal metabolic function. We mimicked the fluctuations in eight healthy young men [25.0 ± 0.1 yr (mean ± SE); body mass index: 25.7 ± 0.4 kg/m2] by subjecting them to intermittent fasting every second day for 20 h for 15 days. Euglycemic hyperinsulinemic (40 mU·min−1·m−2) clamps were performed before and after the intervention period. Subjects maintained body weight (86.4 ± 2.3 kg; coefficient of variation: 0.8 ± 0.1%). Plasma free fatty acid and β-hydroxybutyrate concentrations were 347 ± 18 and 0.06 ± 0.02 mM, respectively, after overnight fast but increased ( P < 0.05) to 423 ± 86 and 0.10 ± 0.04 mM after 20-h fasting, confirming that the subjects were fasting. Insulin-mediated whole body glucose uptake rates increased from 6.3 ± 0.6 to 7.3 ± 0.3 mg·kg−1·min−1 ( P = 0.03), and insulin-induced inhibition of adipose tissue lipolysis was more prominent after than before the intervention ( P = 0.05). After the 20-h fasting periods, plasma adiponectin was increased compared with the basal levels before and after the intervention (5,922 ± 991 vs. 3,860 ± 784 ng/ml, P = 0.02). This experiment is the first in humans to show that intermittent fasting increases insulin-mediated glucose uptake rates, and the findings are compatible with the thrifty gene concept.

Physical inactivity is a risk factor for insulin resistance. We examined the effect of 9 days of bed rest on basal and insulin-stimulated expression of genes potentially involved in insulin action by applying hypothesis-generating microarray in parallel with candidate gene real-time PCR approaches in 20 healthy young men. Furthermore, we investigated whether bed rest affected DNA methylation in the promoter region of the peroxisome proliferator-activated receptor-γ coactivator-1α ( PPARGC1A) gene. Subjects were reexamined after 4 wk of retraining. We found that bed rest induced insulin resistance and altered the expression of more than 4,500 genes. These changes were only partly normalized after 4 wk of retraining. Pathway analyses revealed significant downregulation of 34 pathways, predominantly those of genes associated with mitochondrial function, including PPARGC1A. Despite induction of insulin resistance, bed rest resulted in a paradoxically increased response to acute insulin stimulation in the general expression of genes, particularly those involved in inflammation and endoplasmatic reticulum (ER) stress. Furthermore, bed rest changed gene expressions of several insulin resistance and diabetes candidate genes. We also observed a trend toward increased PPARGC1A DNA methylation after bed rest. We conclude that impaired expression of PPARGC1A and other genes involved in mitochondrial function as well as a paradoxically increased response to insulin of genes involved in inflammation and ER stress may contribute to the development of insulin resistance induced by bed rest. Lack of complete normalization of changes after 4 wk of retraining underscores the importance of maintaining a minimum of daily physical activity.

In this study, the hypothesis that the release of interleukin (IL)‐6 from human muscle is linked to exercise intensity and muscle glucose uptake was investigated. In the overnight fasted state, seven healthy males performed knee extension exercise, kicking with both legs, each at 25 % of maximal power (W_max) for 45 min (eliciting 23 ± 1 % of pulmonary maximal oxygen uptake, V̇_O2,max) and then simultaneously with one leg at 65 % and the other leg at 85 % W_max for 35 min (40 ± 1 % of pulmonary V̇_O2,max). Blood was sampled from a femoral artery and both femoral veins, and blood flow was determined by thermodilution. Thigh plasma flow (0.15 ± 0.01, 1.4 ± 0.2, 2.0 ± 0.1 and 2.3 ± 0.2 l min⁻¹ thigh⁻¹ at rest and 25 %, 65 % and 85 % W_max, respectively) and thigh oxygen uptake (0.02 ± 0.01, 0.27 ± 0.03, 0.48 ± 0.04 and 0.55 ± 0.05 l min⁻¹ thigh⁻¹ at rest and 25 %, 65 % and 85 % W_max, respectively) increased with increasing exercise intensity (P < 0.05). Also, thigh IL‐6 release (0.4 ± 0.1, 1.3 ± 0.5, 1.5 ± 0.6 and 2.5 ± 0.7 ng min⁻¹ thigh⁻¹ at rest and 25 %, 65 % and 85 % W_max, respectively) and thigh glucose uptake (0.05 ± 0.01, 0.3 ± 0.05, 0.75 ± 0.16, 1.07 ± 0.15 mmol min⁻¹ thigh⁻¹ at rest and 25 %, 65 % and 85 % W_max, respectively) increased with increasing exercise intensity (P < 0.05). During the last 35 min of exercise, arterial catecholamine concentrations were higher (P < 0.05) than at rest and during low‐intensity exercise. During exercise, thigh IL‐6 release was positively related to both thigh glucose uptake (P < 0.001) and thigh glucose delivery (P < 0.005), but not to thigh glucose extraction. Thigh IL‐6 release was also positively related to arterial plasma adrenaline concentration. The pre‐exercise muscle glycogen concentration tended to correlate with the arteriovenous IL‐6 concentration difference at rest, and the postexercise glycogen concentration was inversely correlated with IL‐6 release during the final 35 min of exercise. In conclusion, the study indicates that IL‐6 release from human muscle is positively related to exercise intensity, arterial adrenaline concentration and muscle glucose uptake. This supports the hypothesis that IL‐6 may be linked to the regulation of glucose homeostasis during exercise. The observation of a relationship between IL‐6 release and muscle glycogen store both at rest and after exercise suggests that IL‐6 may act as a carbohydrate sensor.