Berthil F Clasen

Aarhus University, Aarhus, Central Jutland, Denmark

Are you Berthil F Clasen?

Claim your profile

Publications (11)50.65 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: Data from transgenic animal models suggest that exercise-induced autophagy is critical for adaptation to physical training, and that Unc-51 like kinase-1 (ULK1) serves as an important regulator of autophagy. Phosphorylation of ULK1 at Ser(555) stimulates autophagy whereas phosphorylation at Ser(757) is inhibitory. To determine if exercise regulates ULK1 phosphorylation in humans in vivo in a nutrient-dependent manner, we examined skeletal muscle biopsies from healthy humans after 1 hour cycling exercise at 50% VO2-max on two occasions: 1) during a 36 hour fast and 2) during continuous glucose infusion at 0.2 g/kg/h. Physical exercise increased ULK1 phosphorylation at Ser(555) and decreased lipidation of Light Chain 3B (LC3B). ULK1 phosphorylation at Ser(555) correlated positively with AMPKα Thr(172) phosphorylation and negatively with LC3B lipidation. ULK1 phosphorylation at Ser(757) was not affected by exercise. Fasting increased ULK1 and p62 protein expression, but did not affect exercise-induced ULK1 phosphorylation. These data demonstrate that autophagy signaling is activated in human skeletal muscle after 60 minutes of exercise independently of nutritional status and suggest that initiation of autophagy constitutes an important physiological response to exercise in humans. Copyright © 2014, Journal of Applied Physiology.
    Journal of Applied Physiology 02/2015; 118(8):jap.01116.2014. DOI:10.1152/japplphysiol.01116.2014 · 3.06 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Context: Growth hormone (GH) secretion is reduced in obesity despite normal serum insulin-like growth factor I (IGF-I) levels but the association between obesity and GH signaling is unknown. Furthermore, SIRT1, a NAD-dependent protein deacetylase, reduces hepatic IGF-I production in mice via blunting of GH-induced STAT5 signaling. Objective: To study GH signaling in muscle and fat in obese subjects and interaction with concomitant administration of the putative SIRT1 activator resveratrol, and to assess the effects of inhibiting or knocking down SIRT1 on GH regulated genes in vitro. Design and participants: 24 obese males were examined in a randomized, double blinded, parallel-group study with resveratrol or placebo treatment for 5 weeks followed by a GH bolus. Muscle and fat biopsies were collected before and after GH. Body composition was assessed by DEXA and MRI. Main Outcome Measure: 1) Effect of body composition and age on GH-stimulated STAT5b phosphorylation and IGF-I, SOCS2, and CISH mRNA in muscle and fat. 2) Impact of resveratrol treatment on GH activity. 3) Impact of inhibiting or knocking down SIRT1 on effects of GH in vitro. Results: Significant GH-induced STAT5b phosphorylation in muscle and fat in obese subjects was recorded together with increased CISH and SOCS2 mRNA. GH-induced STAT5b phosphorylation in muscle correlated positively with age [r=0.53, p<0.01], but not with body composition. Resveratrol administration had no impact on body composition, serum IGF-I, or GH signaling in vivo, and SIRT1 knock down or inhibition did not affect GH signaling in vitro. Conclusion: 1) GH induced STAT5b phosphorylation is detectable in muscle and fat in adult males with simple obesity, but is not determined by body composition. 2) Resveratrol supplementation does not impact circulating IGF-I levels or GH signaling in human muscle and fat. 3) Our data speak against a major impact of SIRT1on GH action in human subjects.
    Journal of Clinical Endocrinology &amp Metabolism 07/2014; 99(12):jc20142215. DOI:10.1210/jc.2014-2215 · 6.21 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Aim Fasting is characterised by profound changes in energy metabolism including progressive loss of body proteins. The underlying mechanisms are however unknown and we therefore determined the effects of a 72-hour-fast on human skeletal muscle protein metabolism and activation of mammalian target of rapamycin (mTOR), a key regulator of cell growth. Methods Eight healthy male volunteers were studied twice: in the postabsorptive state and following 72 hours of fasting. Regional muscle amino acid kinetics was measured in the forearm using amino acid tracers. Signaling to protein synthesis and breakdown were assessed in skeletal muscle biopsies obtained during non-insulin and insulin stimulated conditions on both examination days. Results Fasting significantly increased forearm net phenylalanine release and tended to decrease phenylalanine rate of disappearance. mTOR phosphorylation was decreased by ∼50% following fasting, together with reduced downstream phosphorylation of 4EBP1, ULK1 and rpS6. In addition, the insulin stimulated increase in mTOR and rpS6 phosphorylation was significantly reduced after fasting indicating insulin resistance in this part of the signaling pathway. Autophagy initiation is in part regulated by mTOR through ULK1 and fasting increased expression of the autophagic marker LC3B-II by ∼30%. p62 is degraded during autophagy but was increased by ∼10% during fasting making interpretation of autophagic flux problematic. MAFbx and MURF1 ubiquitin ligases remained unaltered after fasting indicating no change in protesomal protein degradation. Conclusions Our results show that during fasting increased net phenylalanine release in skeletal muscle is associated to reduced mTOR activation and concomitant decreased downstream signaling to cell growth.
    PLoS ONE 07/2014; 9(7):e102031. DOI:10.1371/journal.pone.0102031 · 3.23 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The mammalian target of rapamycin complex 1 (mTORC1) is considered an important role in the muscular adaptations to exercise. It has been proposed that exercise-induced signaling to mTORC1 do not require classic growth factor PI3K/Akt signaling. Activation of IKKβ and the mitogen-activated protein kinases (MAPKs) Erk1/2 and p38 has been suggested to link inflammation and cellular stress to activation of mTORC1 through the tuberous sclerosis 1 (TSC1)/tuberous sclerosis 2 (TSC2) complex. Consequently, activation of these proteins constitutes potential alternative mechanisms of mTORC1 activation following exercise. Previously, we demonstrated that mTOR is preferentially activated in response to resistance exercise compared to endurance exercise in trained individuals without concomitant activation of Akt. In the present study, we extended this investigation by examining IκB kinase complex (IKK), TSC1, MAPK, and upstream Akt activators, along with gene expression of selected cytokines, in skeletal muscles from these subjects. Biopsies were sampled prior to, immediately after, and in the recovery period following resistance exercise, endurance exercise, and control interventions. The major finding was that IKKβ phosphorylation increased exclusively after resistance exercise. No changes in TSC1, Erk1/2, insulin receptor, or insulin receptor substrate 1 phosphorylation were observed in any of the groups, while p38 phosphorylation was higher in the resistance exercise group compared to both other groups immediately after the intervention. Resistance and endurance exercise increased IL6, IL8, and TNFα gene expression immediately after exercise. The non-exercise control group demonstrated that cytokine gene expression is also sensitive to repeated biopsy sampling, whereas no effect of repeated biopsy sampling on protein expression and phosphorylation was observed. In conclusion, resistance exercise, but not endurance exercise, increases IKKβ phosphorylation in trained human subjects, which support the idea that IKKβ can influence the activation of mTORC1 in human skeletal muscle.
    Pflügers Archiv - European Journal of Physiology 07/2013; 465(12). DOI:10.1007/s00424-013-1318-9 · 4.10 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Growth hormone (GH) acutely stimulates lipolysis and fat oxidation, a process which operates postabsorptively and involves activation of the JAK-STAT pathway in the target tissue; no in vivo data exist regarding subsequent GH-regulated gene transcription. We obtained serum samples and muscle biopsies in human subjects before and 2 h after administration of a GH bolus. A significant 75 % elevation in serum FFA levels was recorded post GH. Microarray identified 79 GH-regulated genes in muscle. With qRT-PCR we then examined the expression of selected genes in the presence and absence of glucose-induced suppression of lipolysis. Four genes involved in the JAK-STAT5 signaling pathway were regulated by GH, including SOCS1-3 and CISH, in addition to three genes associated with insulin action: NFkB1A, PIK3C2B, and PRKAG2. The gene encoding ANGPTL4, a protein involved in lipolysis and suppression of LPL activity, exhibited the most pronounced up regulation (5.6 fold) after GH, which was abrogated by concomitant suppression of lipolysis. The GH-induced stimulation of ANGPTL4 gene expression therefore seems secondary to induction of lipolysis. This new concept would imply that abundant supply of circulating FFA would decrease the need for alternative triglyceride derived FFA through distinct inhibition of LPL mediated by increased ANGPTL4 gene expression in human muscle.
    The Journal of Lipid Research 04/2013; 54(7). DOI:10.1194/jlr.P034520 · 4.42 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Obesity, diabetes, hypertension, and hyperlipidemia constitute risk factors for morbidity and premature mortality. Based on animal and in vitro studies, resveratrol reverts these risk factors via stimulation of silent mating type information regulation 2 homolog 1 (SIRT1), but data in human subjects are scarce. The objective of this study was to examine the metabolic effects of high-dose resveratrol in obese human subjects. In a randomized, placebo-controlled, double-blinded, and parallel-group design, 24 obese but otherwise healthy men were randomly assigned to 4 weeks of resveratrol or placebo treatment. Extensive metabolic examinations including assessment of glucose turnover and insulin sensitivity (hyperinsulinemic euglycemic clamp) were performed before and after the treatment. Insulin sensitivity, the primary outcome measure, deteriorated insignificantly in both groups. Endogenous glucose production and the turnover and oxidation rates of glucose remained unchanged. Resveratrol supplementation also had no effect on blood pressure; resting energy expenditure; oxidation rates of lipid; ectopic or visceral fat content; or inflammatory and metabolic biomarkers. The lack of effect disagrees with persuasive data obtained from rodent models and raises doubt about the justification of resveratrol as a human nutritional supplement in metabolic disorders.
    Diabetes 11/2012; 62(4). DOI:10.2337/db12-0975 · 8.10 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Obesity is associated with a markedly increased risk of nonalcoholic fatty liver disease. The anti-inflammatory polyphenol resveratrol possess promising properties in preventing this metabolic condition by dampening the pathological inflammatory reaction in the hepatic tissue. However, in the current study, we hypothesize that the beneficial effect of resveratrol is not solely attributable to its anti-inflammatory potential. Eight-week-old male Wistar rats were randomly distributed into 3 groups of 12 animals each: control diet (C), high-fat diet (HF), and HF supplemented with 100 mg resveratrol daily (HFR). After 8 weeks of dietary treatment, the rats were euthanized and relevant tissues were prepared for subsequent analysis. Resveratrol prevented the high fat-induced steatosis assessed by semiquantitative grading, which furthermore corresponded with a complete normalization of the hepatic triglyceride content (P < .001), despite no change in total body fat. In HFR, the hepatic uncoupling protein 2 expression was significantly increased by 76% and 298% as compared with HF and C, respectively. Moreover, the hepatic mitochondria content in HFR was significantly higher as compared with both C and HF (P < .001 and P = .004, respectively). We found no signs of hepatic inflammation, hereby demonstrating that resveratrol protects against fatty liver disease independently of its proposed anti-inflammatory potential. Our data might indicate that an increased number of mitochondria and, particularly, an increase in hepatic uncoupling protein 2 expression are involved in normalizing the hepatic fat content due to resveratrol supplementation in rodents fed a high-fat diet.
    Nutrition research 09/2012; 32(9):701-8. DOI:10.1016/j.nutres.2012.08.004 · 2.47 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: During fasting, human skeletal muscle depends on lipid oxidation for its energy substrate metabolism. This is associated with the development of insulin resistance and a subsequent reduction of insulin-stimulated glucose uptake. The underlying mechanisms controlling insulin action on skeletal muscle under these conditions are unresolved. In a randomized design, we investigated eight healthy subjects after a 72-h fast compared with a 10-h overnight fast. Insulin action on skeletal muscle was assessed by a hyperinsulinemic euglycemic clamp and by determining insulin signaling to glucose transport. In addition, substrate oxidation, skeletal muscle lipid content, regulation of glycogen synthesis, and AMPK signaling were assessed. Skeletal muscle insulin sensitivity was reduced profoundly in response to a 72-h fast and substrate oxidation shifted to predominantly lipid oxidation. This was associated with accumulation of both lipid and glycogen in skeletal muscle. Intracellular insulin signaling to glucose transport was impaired by regulation of phosphorylation at specific sites on AS160 but not TBC1D1, both key regulators of glucose uptake. In contrast, fasting did not impact phosphorylation of AMPK or insulin regulation of Akt, both of which are established upstream kinases of AS160. These findings show that insulin resistance in muscles from healthy individuals is associated with suppression of site-specific phosphorylation of AS160, without Akt or AMPK being affected. This impairment of AS160 phosphorylation, in combination with glycogen accumulation and increased intramuscular lipid content, may provide the underlying mechanisms for resistance to insulin in skeletal muscle after a prolonged fast.
    AJP Endocrinology and Metabolism 01/2012; 302(2):E190-200. DOI:10.1152/ajpendo.00207.2011 · 3.79 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Evidence suggests that somatostatin not only inhibits the secretion of GH but also suppresses GH action in peripheral tissues. We tested the hypothesis that somatostatin suppresses GH activity in human skeletal muscle in vivo. Eight healthy young men (25.3 ± 2.8 yr) were studied on a single occasion after an overnight fast for 4 h [including a basal period (0-2 h) and a hyperinsulinemic euglycemic clamp (2-4 h)] during an iv GH infusion (50 ng/kg⁻¹ · min⁻¹). Each subject received an intraarterial somatostatin infusion (150 μg/h⁻¹) into one femoral artery and an intraarterial saline infusion into the contra lateral artery. The simultaneous blood samples were drawn from both femoral veins. Muscle biopsies were obtained from one leg at t = 0 and from both legs during the basal period and during the clamp. Muscle glucose uptake, signaling proteins for GH (phosphorylated signal transducer and activator of transcription-5) and insulin (phosphorylation of AS160), and expression of GH-regulated genes (IGF-I and suppressor of cytokine signaling 1-3) were measured. Somatostatin significantly increased glucose uptake measured by arteriovenous glucose difference during the basal period (P = 0.03) but not during the clamp. There was a tendency for the phosphorylation of AS160 to be higher in the somatostatin-infused leg compared with the saline leg (P = 0.055). The expression of suppressor of cytokine signaling-1 mRNA was significantly elevated in the clamp-biopsy from the saline-infused leg (P = 0.024). We concluded the following: 1) in the presence of systemic GH exposure, somatostatin increases basal glucose uptake and reduces the expression of GH-regulated genes directly in skeletal muscle; 2) this supports the concept that somatostatin suppresses GH activity in peripheral tissues, and 3) this may add to the therapeutic effects of somataostatin analogs.
    The Journal of Clinical Endocrinology and Metabolism 06/2011; 96(8):2581-9. DOI:10.1210/jc.2011-0592 · 6.21 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: It is clinically relevant and of physiological interest to investigate whether GH-induced insulin resistance depends on the timing of GH exposure relative to when insulin sensitivity is assessed. GH-induced insulin resistance is rapidly reversible. Eight male GH-deficient patients underwent a 6-h euglycemic-hyperinsulinemic glucose clamp thrice in a randomized crossover design receiving either no GH (study 0), a 7-h GH infusion (0.2-0.3 mg in total) that terminated 5 h before the clamp (study 1), or a similar GH infusion timed to continue during the first hour of the clamp (study 2). A muscle biopsy was obtained 30 min into the clamp. The patients were compared with eight healthy untreated control subjects (study c). The glucose infusion rate, indirect calorimetry, and free fatty acid metabolism were assessed. In muscle biopsies, protein phosphorylation of signal transducer and activator of transcription 5, Akt, and Akt substrate 160 (phospho-Akt substrate signal) and gene expression of IGF-I and SOCS1-3 were assessed. Insulin sensitivity differed significantly between the GH-deficiency studies (P = 0.005) with distinct insulin resistance in study 2 and increased insulin sensitivity in study 0 [area under the glucose infusion rate curve (mg/kg · min): 1663 ± 151 (study 0) vs. 1482 ± 166 (study 1) vs. 1123 ± 136 (study 2) vs. 1492 ± 229 (control group)]. Free fatty acid levels and lipid oxidation were elevated in response to GH exposure but became suppressed during the clamp. IGF-I and SOCS3 gene expression was increased in study 2. Very-low-dose GH exposure evokes acute insulin resistance that subsides after 5 h. This time-dependent reversibility should be considered when assessing the impact of GH on glucose homeostasis.
    The Journal of Clinical Endocrinology and Metabolism 05/2011; 96(8):2548-57. DOI:10.1210/jc.2011-0273 · 6.21 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Skeletal muscle is the major constituent of lean body mass and a major determinant of energy expenditure both at rest and during physical activity. Growth hormone, in turn, influences muscle mass as well as energy expenditure. Growth hormone substitution in adults increases muscle mass by 5-10%, but part of the effect is attributed to rehydration rather than protein accretion. In addition, GH regulates substrate metabolism in muscle and in particular antagonizes insulin-stimulated glucose disposal. This effect is linked to increased free fatty acid (FFA) flux but the molecular mechanisms remain unclear. During fasting, GH-induced insulin resistance may be favorable by reducing the demand of gluconeogenesis from protein. But in the postprandial phase, GH exposure may compromise glucose tolerance via the same mechanisms. Understanding the mechanisms whereby GH antagonizes insulin-stimulated glucose disposal in muscle is an important future research field with implications for a variety of clinical conditions ranging from malnutrition to obesity and type 2 diabetes.
    Pediatric Nephrology 11/2009; 25(4):705-9. DOI:10.1007/s00467-009-1334-3 · 2.86 Impact Factor

Publication Stats

223 Citations
50.65 Total Impact Points


  • 2014-2015
    • Aarhus University
      • • Medical Research Laboratories
      • • Department of Clinical Medicine
      Aarhus, Central Jutland, Denmark
  • 2009-2014
    • Aarhus University Hospital
      • • Department of Endocrinology and Internal Medicine
      • • Institute of Clinical Medicine
      Aarhus, Central Jutland, Denmark

We use cookies to give you the best possible experience on ResearchGate. Read our cookies policy to learn more.