Insulin sensitivity and fat mass in young male sedentary adults

We live in an obesogenic environment, spending a lot of time sitting neglecting physical activity. This study aims to determine the impact of a sedentary lifestyle on insulin sensitivity by comparing insulin sensitivity of healthy athletes and sedentary subjects. Twelve athletes and 12 sedentary subjects underwent a two-step hyperinsulinemic euglycemic clamp test to assess insulin sensitivity and a DEXA scan to assess body fat mass. Insulin sensitivity was significantly lower in sedentary subjects (p=0.009) and fat mass negatively correlated with insulin sensitivity (r=-0.57, p=0.005). This study shows that healthy sedentary subjects have an impaired insulin metabolism compared to trained athletes

The effect of UCP3 overexpression on mitochondrial ROS production in skeletal muscle of young versus aged mice

AbstractUncoupling protein 3 (UCP3) is suggested to protect mitochondria against aging and lipid-induced damage, possibly via modulation of reactive oxygen species (ROS) production. Here we show that mice overexpressing UCP3 (UCP3Tg) have a blunted age-induced increase in ROS production, assessed by electron spin resonance spectroscopy, but only after addition of 4-hydroxynonenal (4-HNE). Mitochondrial function, assessed by respirometry, on glycolytic substrate was lower in UCP3Tg mice compared to wild types, whereas this tended to be higher on fatty acids. State 4o respiration was higher in UCP3Tg animals. To conclude, UCP3 overexpression leads to increased state 4o respiration and, in presence of 4-HNE, blunts the age-induced increase in ROS production

MicroRNA-204-5p modulates mitochondrial biogenesis in C2C12 myotubes and associates with oxidative capacity in humans

Using an unbiased high-throughput microRNA (miRNA)-silencing screen combined with functional readouts for mitochondrial oxidative capacity in C2C12 myocytes, we previously identified 19 miRNAs as putative regulators of skeletal muscle mitochondrial metabolism. In the current study, we highlight miRNA-204-5p, identified from this screen, and further studied its role in the regulation of skeletal muscle mitochondrial function. Following silencing of miRNA-204-5p in C2C12 myotubes, gene and protein expression were assessed using quantitative polymerase chain reaction, microarray analysis, and western blot analysis, while morphological changes were studied by confocal microscopy. In addition, miRNA-204-5p expression was quantified in human skeletal muscle biopsies and associated with in vivo mitochondrial oxidative capacity. Transcript levels of PGC-1α (3.71-fold; p <.01), predicted as an miR-204-5p target, as well as mitochondrial DNA copy number (p <.05) and citrate synthase activity (p =.06) were increased upon miRNA-204-5p silencing in C2C12 myotubes. Silencing of miRNA-204-5p further resulted in morphological changes, induced gene expression of autophagy marker light chain 3 protein b (LC3B; q =.05), and reduced expression of the mitophagy marker FUNDC1 (q =.01). Confocal imaging revealed colocalization between the autophagosome marker LC3B and the mitochondrial marker OxPhos upon miRNA-204-5p silencing. Finally, miRNA-204-5p was differentially expressed in human subjects displaying large variation in oxidative capacity and its expression levels associated with in vivo measures of skeletal muscle mitochondrial function. In summary, silencing of miRNA-204-5p in C2C12 myotubes stimulated mitochondrial biogenesis, impacted on cellular morphology, and altered expression of markers related to autophagy and mitophagy. The association between miRNA-204-5p and in vivo mitochondrial function in human skeletal muscle further identifies miRNA-204-5p as an interesting modulator of skeletal muscle mitochondrial metabolism.</p

High Fat Diet-Induced Changes in Mouse Muscle Mitochondrial Phospholipids Do Not Impair Mitochondrial Respiration Despite Insulin Resistance

BACKGROUND: Type 2 diabetes mellitus and muscle insulin resistance have been associated with reduced capacity of skeletal muscle mitochondria, possibly as a result of increased intake of dietary fat. Here, we examined the hypothesis that a prolonged high-fat diet consumption (HFD) increases the saturation of muscle mitochondrial membrane phospholipids causing impaired mitochondrial oxidative capacity and possibly insulin resistance. METHODOLOGY: C57BL/6J mice were fed an 8-week or 20-week low fat diet (10 kcal%; LFD) or HFD (45 kcal%). Skeletal muscle mitochondria were isolated and fatty acid (FA) composition of skeletal muscle mitochondrial phospholipids was analyzed by thin-layer chromatography followed by GC. High-resolution respirometry was used to assess oxidation of pyruvate and fatty acids by mitochondria. Insulin sensitivity was estimated by HOMA-IR. PRINCIPAL FINDINGS: At 8 weeks, mono-unsaturated FA (16∶1n7, 18∶1n7 and 18∶1n9) were decreased (-4.0%, p<0.001), whereas saturated FA (16∶0) were increased (+3.2%, p<0.001) in phospholipids of HFD vs. LFD mitochondria. Interestingly, 20 weeks of HFD descreased mono-unsaturated FA while n-6 poly-unsaturated FA (18∶2n6, 20∶4n6, 22∶5n6) showed a pronounced increase (+4.0%, p<0.001). Despite increased saturation of muscle mitochondrial phospholipids after the 8-week HFD, mitochondrial oxidation of both pyruvate and fatty acids were similar between LFD and HFD mice. After 20 weeks of HFD, the increase in n-6 poly-unsaturated FA was accompanied by enhanced maximal capacity of the electron transport chain (+49%, p = 0.002) and a tendency for increased ADP-stimulated respiration, but only when fuelled by a lipid-derived substrate. Insulin sensitivity in HFD mice was reduced at both 8 and 20 weeks. CONCLUSIONS/INTERPRETATION: Our findings do not support the concept that prolonged HF feeding leads to increased saturation of skeletal muscle mitochondrial phospholipids resulting in a decrease in mitochondrial fat oxidative capacity and (muscle) insulin resistance

The influence of bright and dim light on substrate metabolism, energy expenditure and thermoregulation in insulin-resistant individuals depends on time of day

AIMS/HYPOTHESIS: In our modern society, artificial light is available around the clock and most people expose themselves to electrical light and light-emissive screens during the dark period of the natural light/dark cycle. Such suboptimal lighting conditions have been associated with adverse metabolic effects, and redesigning indoor lighting conditions to mimic the natural light/dark cycle more closely holds promise to improve metabolic health. Our objective was to compare metabolic responses to lighting conditions that resemble the natural light/dark cycle in contrast to suboptimal lighting in individuals at risk of developing metabolic diseases. METHODS: Therefore, we here performed a non-blinded, randomised, controlled, crossover trial in which overweight insulin-resistant volunteers (n = 14) were exposed to two 40 h laboratory sessions with different 24 h lighting protocols while staying in a metabolic chamber under real-life conditions. In the Bright day–Dim evening condition, volunteers were exposed to electric bright light (~1250 lx) during the daytime (08:00–18:00 h) and to dim light (~5 lx) during the evening (18:00–23:00 h). Vice versa, in the Dim day–Bright evening condition, volunteers were exposed to dim light during the daytime and bright light during the evening. Randomisation and allocation to light conditions were carried out by sequential numbering. During both lighting protocols, we performed 24 h indirect calorimetry, and continuous core body and skin temperature measurements, and took frequent blood samples. The primary outcome was plasma glucose focusing on the pre- and postprandial periods of the intervention. RESULTS: Spending the day in bright light resulted in a greater increase in postprandial triacylglycerol levels following breakfast, but lower glucose levels preceding the dinner meal at 18:00 h, compared with dim light (5.0 ± 0.2 vs 5.2 ± 0.2 mmol/l, n = 13, p=0.02). Dim day–Bright evening reduced the increase in postprandial glucose after dinner compared with Bright day–Dim evening (incremental AUC: 307 ± 55 vs 394 ± 66 mmol/l × min, n = 13, p=0.009). After the Bright day–Dim evening condition the sleeping metabolic rate was identical compared with the baseline night, whereas it dropped after Dim day–Bright evening. Melatonin secretion in the evening was strongly suppressed for Dim day–Bright evening but not for Bright day–Dim evening. Distal skin temperature for Bright day–Dim evening was lower at 18:00 h (28.8 ± 0.3°C vs 29.9 ± 0.4°C, n = 13, p=0.039) and higher at 23:00 h compared with Dim day–Bright evening (30.1 ± 0.3°C vs 28.8 ± 0.3°C, n = 13, p=0.006). Fasting and postprandial plasma insulin levels and the respiratory exchange ratio were not different between the two lighting protocols at any time. CONCLUSIONS/INTERPRETATION: Together, these findings suggest that the indoor light environment modulates postprandial substrate handling, energy expenditure and thermoregulation of insulin-resistant volunteers in a time-of-day-dependent manner. TRIAL REGISTRATION: ClinicalTrials.gov NCT03829982. FUNDING: We acknowledge the financial support from the Netherlands Cardiovascular Research Initiative: an initiative with support from the Dutch Heart Foundation (CVON2014–02 ENERGISE). GRAPHICAL ABSTRACT: [Image: see text] SUPPLEMENTARY INFORMATION: The online version contains peer-reviewed but unedited supplementary material available at 10.1007/s00125-021-05643-9

The importance of 24-h metabolism in obesity-related metabolic disorders: opportunities for timed interventions

Various metabolic processes in the body oscillate throughout the natural day, driven by a biological clock. Circadian rhythms are also influenced by time cues from the environment (light exposure) and behaviour (eating and exercise). Recent evidence from diurnal- and circadian-rhythm studies indicates rhythmicity in various circulating metabolites, insulin secretion and -sensitivity and energy expenditure in metabolically healthy adults. These rhythms have been shown to be disturbed in adults with obesity-related metabolic disturbances. Moreover, eating and being (in)active at a time that the body is not prepared for it, as in night-shift work, is related to poor metabolic outcomes. These findings indicate the relevance of 24-h metabolism in obesity-related metabolic alterations and have also led to novel strategies, such as timing of food intake and exercise, to reinforce the circadian rhythm and thereby improving metabolic health. This review aims to deepen the understanding of the influence of the circadian system on metabolic processes and obesity-related metabolic disturbances and to discuss novel time-based strategies that may be helpful in combating metabolic disease

The importance of 24-h metabolism in obesity-related metabolic disorders:opportunities for timed interventions

Various metabolic processes in the body oscillate throughout the natural day, driven by a biological clock. Circadian rhythms are also influenced by time cues from the environment (light exposure) and behaviour (eating and exercise). Recent evidence from diurnal- and circadian-rhythm studies indicates rhythmicity in various circulating metabolites, insulin secretion and -sensitivity and energy expenditure in metabolically healthy adults. These rhythms have been shown to be disturbed in adults with obesity-related metabolic disturbances. Moreover, eating and being (in)active at a time that the body is not prepared for it, as in night-shift work, is related to poor metabolic outcomes. These findings indicate the relevance of 24-h metabolism in obesity-related metabolic alterations and have also led to novel strategies, such as timing of food intake and exercise, to reinforce the circadian rhythm and thereby improving metabolic health. This review aims to deepen the understanding of the influence of the circadian system on metabolic processes and obesity-related metabolic disturbances and to discuss novel time-based strategies that may be helpful in combating metabolic disease