ORCID Profile
0000-0003-3452-1501
Current Organisation
Baker IDI Heart and Diabetes Institute
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Publisher: Wiley
Date: 14-01-2010
DOI: 10.1113/EXPPHYSIOL.2009.049353
Abstract: We have previously demonstrated that well-trained subjects who completed a 3 week training programme in which selected high-intensity interval training (HIT) sessions were commenced with low muscle glycogen content increased the maximal activities of several oxidative enzymes that promote endurance adaptations to a greater extent than subjects who began all training sessions with normal glycogen levels. The aim of the present study was to investigate acute skeletal muscle signalling responses to a single bout of HIT commenced with low or normal muscle glycogen stores in an attempt to elucidate potential mechanism(s) that might underlie our previous observations. Six endurance-trained cyclists/triathletes performed a 100 min ride at approximately 70% peak O(2) uptake (AT) on day 1 and HIT (8 x 5 min work bouts at maximal self-selected effort with 1 min rest) 24 h later (HIGH). Another six subjects, matched for fitness and training history, performed AT on day 1 then 1-2 h later, HIT (LOW). Muscle biopsies were taken before and after HIT. Muscle glycogen concentration was higher in HIGH versus LOW before the HIT (390 +/- 28 versus 256 +/- 67 micromol (g dry wt)(1)). After HIT, glycogen levels were reduced in both groups (P < 0.05) but HIGH was elevated compared with LOW (229 +/- 29 versus 124 +/- 41 micromol (g dry wt)(1) P < 0.05). Phosphorylation of 5 AMP-activated protein kinase (AMPK) increased after HIT, but the magnitude of increase was greater in LOW (P < 0.05). Despite the augmented AMPK response in LOW after HIT, selected downstream AMPK substrates were similar between groups. Phosphorylation of p38 mitogen-activated protein kinase (p38 MAPK) was unchanged for both groups before and after the HIT training sessions. We conclude that despite a greater activation AMPK phosphorylation when HIT was commenced with low compared with normal muscle glycogen availability, the localization and phosphorylation state of selected downstream targets of AMPK were similar in response to the two interventions.
Publisher: Springer Science and Business Media LLC
Date: 23-06-2009
DOI: 10.1007/S00125-009-1420-X
Abstract: Chronic diseases arising from obesity will continue to escalate over coming decades. Current approaches to combating obesity include lifestyle measures, surgical interventions and drugs that target weight reduction or the metabolic consequences of obesity. Lifestyle measures including physical activity are usually the primary strategy, but these are of limited long-term efficacy because of failure to maintain behavioural change. An alternative approach used to elicit the benefits of exercise training and overcome the problems of long-term compliance is to develop drugs that mimic aspects of the trained state. Elucidation of metabolic pathways responsive to exercise in various tissues, particularly skeletal muscle, was an important antecedent to the promising concept of drugs that may mimic specific aspects of the exercise response. From an obesity perspective, an important aim is to develop an agent that reduces body fat and improves metabolic homeostasis. This review focuses on promising metabolic signalling pathways in skeletal muscle that may yield 'exercise mimetic' targets.
Publisher: MDPI AG
Date: 28-09-2020
Abstract: Brown adipose tissue (BAT) activation is a possible therapeutic strategy to increase energy expenditure and improve metabolic homeostasis in obesity. Recent studies have revealed novel interactions between BAT and circulating lipid species—in particular, the non-esterified fatty acid (NEFA) and oxylipin lipid classes. This study aimed to identify in idual lipid species that may be associated with cold-stimulated BAT activity in humans. A panel of 44 NEFA and 41 oxylipin species were measured using mass-spectrometry-based lipidomics in the plasma of fourteen healthy male participants before and after 90 min of mild cold exposure. Lipid measures were correlated with BAT activity measured via 18F-fluorodeoxyglucose ([18F]FDG) positron emission tomography/computed tomography (PET/CT), along with norepinephrine (NE) concentration (a surrogate marker of sympathetic activity). The study identified a significant increase in total NEFA concentration following cold exposure that was positively associated with NE concentration change. In idually, 33 NEFA and 11 oxylipin species increased significantly in response to cold exposure. The concentration of the omega-3 NEFA, docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) at baseline was significantly associated with BAT activity, and the cold-induced change in 18 NEFA species was significantly associated with BAT activity. No significant associations were identified between BAT activity and oxylipins.
Publisher: Wiley
Date: 08-2009
Publisher: Springer Science and Business Media LLC
Date: 18-10-2017
DOI: 10.1007/S00125-017-4479-9
Abstract: Increasing brown adipose tissue (BAT) activity is a possible therapeutic strategy to increase energy expenditure and glucose and lipid clearance to ameliorate obesity and associated comorbidities. The thiazolidinedione (TZD) class of glucose-lowering drugs increase BAT browning in preclinical experimental models but whether these actions extend to humans in vivo is unknown. The aim of this study was to determine the effect of pioglitazone treatment on adipocyte browning and adaptive thermogenesis in humans. We first examined whether pioglitazone treatment of cultured human primary subacromioclavicular-derived adipocytes induced browning. Then, in a blinded, placebo-controlled, parallel trial, conducted within the Baker Institute clinical research laboratories, 14 lean male participants who were free of cardiometabolic disease were randomised to receive either placebo (lactose n = 7, age 22 ± 1 years) or pioglitazone (45 mg/day, n = 7, age 21 ± 1 years) for 28 days. Participants were allocated to treatments by Alfred Hospital staff independent from the study via electronic generation of a random number sequence. Researchers conducting trials and analysing data were blind to treatment allocation. The change in cold-stimulated BAT activity, assessed before and after the intervention by [ Pioglitazone significantly increased in vitro browning and adipogenesis of adipocytes. In the clinical trial, cold-induced BAT maximum standardised uptake value was significantly reduced after pioglitazone compared with placebo (-57 ± 6% vs -12 ± 18%, respectively p < 0.05). BAT total glucose uptake followed a similar but non-significant trend (-50 ± 10% vs -6 ± 24%, respectively p = 0.097). Pioglitazone increased total and lean body mass compared with placebo (p < 0.05). No other changes between groups were detected. The disparity in the actions of pioglitazone on BAT between preclinical experimental models and our in vivo human trial highlight the imperative to conduct human proof-of-concept studies as early as possible in BAT research programmes aimed at therapeutic development. Our clinical trial findings suggest that reduced BAT activity may contribute to weight gain associated with pioglitazone and other TZDs. ClinicalTrials.gov NCT02236962 FUNDING: This work was supported by the Diabetes Australia Research Program and OIS scheme from the Victorian State Government.
Publisher: American Physiological Society
Date: 03-2004
Publisher: Public Library of Science (PLoS)
Date: 21-02-2013
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 05-07-2013
DOI: 10.1161/CIRCRESAHA.113.300689
Abstract: High-density lipoprotein cholesterol elevation via cholesteryl ester transfer protein (CETP) inhibition represents a novel therapy for atherosclerosis, which also may have relevance for type 2 diabetes mellitus. The current study assessed the effects of a CETP inhibitor on postprandial insulin, ex vivo insulin secretion, and cholesterol efflux from pancreatic β-cells. Healthy participants received a daily dose of CETP inhibitor (n=10) or placebo (n=15) for 14 days in a randomized double-blind study. Insulin secretion and cholesterol efflux from MIN6N8 β-cells were determined after incubation with treated plasma. CETP inhibition increased plasma high-density lipoprotein cholesterol, apolipoprotein AI, and postprandial insulin. MIN6N8 β-cells incubated with plasma from CETP inhibitor–treated in iduals (compared with placebo) exhibited an increase in both glucose-stimulated insulin secretion and cholesterol efflux over the 14-day treatment period. CETP inhibition increased postprandial insulin and promoted ex vivo β-cell glucose-stimulated insulin secretion, potentially via enhanced β-cell cholesterol efflux.
Publisher: Wiley
Date: 24-09-2019
DOI: 10.1111/DOM.13516
Abstract: To quantify acute energy expenditure, supraclavicular skin temperature and cardiovascular responses to four doses of the β3-adrenoceptor agonist, mirabegron. A total of 17 in iduals (11 men, six women) participated in this ascending-dose study, receiving single 50-, 100-, 150- and 200-mg doses of mirabegron on four separate days with 3 to 14 days wash-out between each dose. All variables were measured each visit from baseline to 180 minutes post mirabegron treatment. To determine brown adipose tissue (BAT) thermogenic efficacy at each dose, energy expenditure and supraclavicular skin temperature were compared from baseline to 180 minutes post mirabegron treatment. To examine safety, changes in cardiovascular variables at 100, 150 and 200 mg were compared with the standard clinical dose of 50 mg. Energy expenditure significantly increased after the 100- (35.6 ± 5.4 kJ/h) and 200-mg (35.6 ± 13.1 kJ/h) doses (P ≤ 0.05), and trended towards an increase after 150 mg (24.1 ± 13.6 kJ/h). Supraclavicular skin temperature increased after 50- (0.22 ± 0.1°C), 100- (0.30 ± 0.1°C) and 150-mg mirabegron doses (0.29 ± 0.1°C P ≤ 0.05). The change in systolic blood pressure was greater after 150- (7.1 ± 1.3 mm Hg) and 200-mg doses (9.3 ± 1.9 mm Hg) than after the 50-mg dose (2.2 ± 1.3 mm Hg P ≤ 0.05). The change in heart rate was greater after 200 mg (9.0 ± 2.2 bpm) compared with 50 mg (2.9 ± 1.4 bpm P ≤ 0.05). A 100-mg dose of mirabegron increases energy expenditure and supraclavicular skin temperature in a β3-adrenoceptor-specific manner, without the off-target elevations in blood pressure or heart rate observed at higher doses.
Publisher: American Physiological Society
Date: 2005
DOI: 10.1152/AJPENDO.00257.2004
Abstract: To determine whether IL-6 increases lipolysis and fat oxidation in patients with type 2 diabetes and/or whether it exerts this effect independently of changes to the hormonal milieu, patients with type 2 diabetes (D) and healthy control subjects (CON) underwent recombinant human (rh)IL-6 infusion for 3 h. Rates of appearance (R a ) and disappearance (R d ) of [U- 13 C]palmitate and [6,6- 2 H 2 ]glucose were determined. rhIL-6 infusion increased ( P 0.05) palmitate R a and R d in a similar fashion in both groups. Neither plasma glucose concentration nor glucose R a /R d was affected by rhIL-6 infusion in either group, whereas rhIL-6 infusion resulted in a reduction ( P 0.05) in circulating insulin in D. Plasma growth hormone (GH) was increased ( P 0.05) by IL-6 in CON, and cortisol increased ( P 0.05) in response to IL-6 in both groups. To determine whether IL-6 was exerting its effect directly or through activation of these hormones, we performed cell culture experiments. Fully differentiated 3T3-L1 adipocytes were treated with PBS (control) IL-6, or IL-6 plus dexamethasone and GH. IL-6 treatment alone increased ( P 0.05) lipolysis, but this effect was reduced by the addition of dexamethasone and GH such that IL-6 plus dexamethasone and GH had blunted ( P 0.05) lipolysis compared with IL-6 alone. To assess whether IL-6 increases fat oxidation, L6 myotubes were treated with PBS (Control), IL-6, or AICAR, a compound known to increase lipid oxidation. Both IL-6 and AICAR markedly increased ( P 0.05) oxidation of [ 14 C]palmitate compared with Control. Acute IL-6 treatment increased fatty acid turnover in D patients as well as healthy CON subjects. Moreover, IL-6 appears to be activating lipolysis independently of elevations in GH and/or cortisol and appears to be a potent catalyst for fat oxidation in muscle cells.
Publisher: Canadian Science Publishing
Date: 2011
DOI: 10.1139/H10-089
Abstract: The performance of prolonged ( min), continuous, endurance exercise is limited by endogenous carbohydrate (CHO) stores. Accordingly, for many decades, sports nutritionists and exercise physiologists have proposed a number of diet-training strategies that have the potential to increase fatty acid availability and rates of lipid oxidation and thereby attenuate the rate of glycogen utilization during exercise. Because the acute ingestion of exogenous substrates (primarily CHO) during exercise has little effect on the rates of muscle glycogenolysis, recent studies have focused on short-term ( –2 weeks) diet-training interventions that increase endogenous substrate stores (i.e., muscle glycogen and lipids) and alter patterns of substrate utilization during exercise. One such strategy is “fat adaptation”, an intervention in which well-trained endurance athletes consume a high-fat, low-CHO diet for up to 2 weeks while undertaking their normal training and then immediately follow this by CHO restoration (consuming a high-CHO diet and tapering for 1–3 days before a major endurance event). Compared with an isoenergetic CHO diet for the same intervention period, this “dietary periodization” protocol increases the rate of whole-body and muscle fat oxidation while attenuating the rate of muscle glycogenolysis during submaximal exercise. Of note is that these metabolic perturbations favouring the oxidation of fat persist even in the face of restored endogenous CHO stores and increased exogenous CHO availability. Here we review the current knowledge of some of the potential mechanisms by which skeletal muscle sustains high rates of fat oxidation in the face of high exogenous and endogenous CHO availability.
Publisher: Springer Science and Business Media LLC
Date: 15-03-2006
DOI: 10.1007/S00125-006-0178-7
Abstract: We compared metabolic gene expression in adipose tissue and skeletal muscle from patients with type 2 diabetes and from well-matched healthy control subjects. We hypothesised that gene expression would be discordantly regulated when comparing the two groups. Our secondary aim was to determine the effect of Interleukin-6 (IL6) infusion on circulating adipokines and on gene expression in human adipose tissue. To do this we used real-time RT-PCR. Both diabetic and control subjects underwent basal skeletal muscle and subcutaneous adipose tissue biopsies. A subset of these in iduals underwent a 3-h infusion of recombinant human IL6 and had adipose tissue s les taken before and after infusion. The mRNA gene expression of suppressor of cytokine signalling (SOCS) 3, peroxisome proliferative activated receptor (PPAR) alpha/delta, PPAR gamma, coactivator 1, alpha (PPARGC1A), carnitine palmitoyltransferase 1B and solute carrier family 2 (facilitated glucose transporter), member 4 (formerly known as glucose transporter 4/GLUT4), was higher in adipose tissue, but lower in skeletal muscle of diabetic patients than in that of control subjects. In addition, uncoupling protein 1 (UCP1) gene was detected in the adipose tissue of some of the diabetic patients, but not in the control subjects. The following genes were increased by infusion of recombinant human IL6 in both groups: SOCS1/3, resistin, adiponectin, AMP-activated protein kinase-alpha-1 and PPARA. Plasma tumour necrosis factor alpha, adiponectin and resistin were all unaffected by IL6 infusion, but plasma resistin was lower in the diabetic subjects than in control subjects. The observation that PPARGC1A and the PPARs were upregulated in the adipose tissue of type 2 diabetic patients, along with the finding that adipose tissue from some patients with type 2 diabetes can express UCP1 mRNA, suggests that in these patients white adipose tissue may move towards a brown adipose tissue phenotype.
Publisher: Wiley
Date: 14-07-2017
DOI: 10.1111/OBR.12584
Abstract: Elevating energy expenditure via adaptive thermogenesis in brown adipose tissue (BAT) is a potential strategy to reverse obesity. Much early enthusiasm for this approach, based on rodent studies, was tempered by the belief that BAT was relatively inconsequential in healthy adult humans. Interest was reinvigorated a decade ago when a series of studies re-identified BAT, primarily in upper thoracic regions, in adults. Despite the ensuing explosion of pre-clinical investigations and identification of an extensive list of potential target molecules for BAT recruitment, our understanding of human BAT physiology remains limited, particularly regarding interventions which might hold therapeutic promise. Cold-induced BAT thermogenesis (CIT) has been well studied, although is not readily translatable as an anti-obesity approach, whereas little is known regarding the role of BAT in human diet-induced thermogenesis (DIT). Furthermore, human studies dedicated to translating known pharmacological mechanisms of adipose browning from animal models are sparse. Several lines of recent evidence suggest that molecular regulation and physiology of human BAT differ to that of laboratory rodents, which form the majority of our knowledge base. This review will summarize knowledge on CIT and expand upon the current understanding and evidence gaps related to human adaptive thermogenesis via mechanisms other than cold.
Publisher: Elsevier BV
Date: 10-2013
DOI: 10.1016/J.PHARMTHERA.2013.05.009
Abstract: Harnessing the considerable capacity of brown adipose tissue (BAT) to consume energy was first proposed as a potential target to control obesity nearly 40years ago. The plausibility of this approach was, however, questioned due to the prevailing view that BAT was either not present or not functional in adult humans. Recent definitive identification of functional BAT in adult humans as well as a number of important advances in the understanding of BAT biology has reignited interest in BAT as an anti-obesity target. Proof-of-concept evidence demonstrating drug-induced BAT activation provides an important foundation for development of targeted pharmacological approaches with clinical application. This review considers evidence from both human and relevant animal studies to determine whether harnessing BAT for the treatment of obesity via pharmacological intervention is a realistic goal.
Publisher: Elsevier BV
Date: 03-2011
DOI: 10.1194/JLR.P012518
Publisher: American Physiological Society
Date: 08-2004
DOI: 10.1152/AJPREGU.00030.2004
Abstract: To determine the expression and induction of cytokines in human skeletal muscle during concentric contractions, eight males performed 60 min of bicycle exercise, with either a normal (Con) or reduced (Lo Gly) preexercise intramuscular glycogen content. Muscle biopsy s les were obtained before and after exercise and analyzed for glycogen and the mRNA expression of 13 cytokines. Resting muscle glycogen was higher ( P 0.05) in Con compared with Lo Gly and was reduced ( P 0.05) to 102 ± 32 vs. 17 ± 5 mmol U glycosyl/kg dry mass for Con and Lo Gly, respectively. We detected mRNA levels in human skeletal muscle for five cytokines, namely interleukin (IL)-1β, IL-6, IL-8, IL-15, and tumor necrosis factor-α. However, muscle contraction increased ( P 0.05) the mRNA expression of IL-6 and IL-8 alone. In addition, the fold change for both IL-8 and IL-6 was markedly higher ( P 0.05) in Lo Gly compared with Con. Given these results, we analyzed venous blood s les, obtained before and during exercise, for IL-6 and IL-8. Plasma IL-6 was not different at rest, and although the circulating concentration of this cytokine increased ( P 0.05) it increased to a greater extent ( P 0.05) throughout exercise in Lo Gly. In contrast, plasma IL-8 was not affected by exercise or treatment. These data demonstrate that cytokines are not ubiquitously expressed in skeletal muscle and that only IL-6 and IL-8 mRNA are increased during contraction of this mode and duration. Furthermore, the mRNA abundance of IL-6 and IL-8 appears to be influenced by glycogen availability in the contracting muscle.
Publisher: Elsevier BV
Date: 06-2016
DOI: 10.1016/J.METABOL.2016.03.002
Abstract: High-density lipoprotein (HDL) and apolipoprotein A-I (apoA-I) can modulate glucose metabolism through multiple mechanisms. This study determined the effects of a novel bromodomain and extra-terminal (BET) inhibitor (RVX-208) and putative apoA-I inducer on lipid species contained within HDL (HDL lipidome) and glucose metabolism. Twenty unmedicated males with prediabetes received 100mg b.i.d. RVX-208 and placebo for 29-33days separated by a wash-out period in a randomized, cross-over design trial. Plasma HDL-cholesterol and apoA-I were assessed as well as lipoprotein particle size and distribution using NMR spectroscopy. An oral glucose tolerance test (OGTT) protocol with oral and infused stable isotope tracers was employed to assess postprandial plasma glucose, indices of insulin secretion and insulin sensitivity, glucose kinetics and lipolysis. Whole plasma and HDL lipid profiles were measured using mass spectrometry. RVX-208 treatment for 4weeks increased 6 sphingolipid and 4 phospholipid classes in the HDL lipidome (p≤0.05 versus placebo), but did not change conventional clinical lipid measures. The concentration of medium-sized HDL particles increased by 11% (P=0.01) and small-sized HDL particles decreased by 10% (P=0.04) after RVX-208 treatment. In response to a glucose load, after RVX-208 treatment, plasma glucose peaked at a similar level to placebo, but 30min later with a more sustained elevation (treatment effect, P=0.003). There was a reduction and delay in total (P=0.001) and oral (P=0.003) glucose rates of appearance in plasma and suppression of endogenous glucose production (P=0.014) after RVX-208 treatment. The rate of glucose disappearance was also lower following RVX-208 (P=0.016), with no effect on glucose oxidation or total glucose disposal. RVX-208 increased 10 lipid classes in the plasma HDL fraction, without altering the concentrations of either apoA-I or HDL-cholesterol (HDL-C). RVX-208 delayed and reduced oral glucose absorption and endogenous glucose production, with plasma glucose maintained via reduced peripheral glucose disposal. If sustained, these effects may protect against the development of type 2 diabetes.
Publisher: Springer Science and Business Media LLC
Date: 07-2004
Publisher: Wiley
Date: 29-10-2012
DOI: 10.1111/J.1440-1681.2012.05732.X
Abstract: Being born preterm and/or small for gestational age are well-established risk factors for cardiometabolic disease in adulthood. Physical activity has the potential to mitigate against the detrimental cardiometabolic effects of low birth weight from two perspectives: (i) maternal exercise prior to and during pregnancy and (ii) exercise during childhood or adulthood for those born small or prematurely. Evidence from epidemiological birth cohort studies suggests that the effects of moderate-intensity physical activity during pregnancy on mean birth weight are small, but reduce the risk of either high or low birth weight infants. In contrast, vigorous and/or high-intensity exercise during pregnancy has been associated with reduced birth weight. In childhood and adolescence, exercise ability is compromised in extremely low birth weight in iduals (< 1000 g), but only marginally reduced in those of very low to low birth weight (1000-2500 g). Epidemiological studies show that the association between birth weight and metabolic disease is lost in physically fit in iduals and, consistently, that the association between low birth weight and metabolic syndrome is accentuated in unfit in iduals. Physical activity intervention studies indicate that most cardiometabolic risk factors respond to exercise in a protective manner, independent of birth weight. The mechanisms by which exercise may protect low birth weight in iduals include restoration of muscle mass, reduced adiposity and enhanced β-cell mass and function, as well as effects on both aerobic and anaerobic muscle metabolism, including substrate utilization and mitochondrial function. Vascular and cardiac adaptations are also likely important, but are less well studied.
Publisher: Public Library of Science (PLoS)
Date: 06-09-2013
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 03-2002
DOI: 10.1097/00005768-200203000-00011
Abstract: To determine the effect of short-term (3-d) fat adaptation on high-intensity exercise training in seven competitive endurance athletes (maximal O2 uptake 5.0 +/- 0.5 L x min(-1), mean +/-SD). Subjects consumed a standardized diet on d-0 then, in a randomized cross-over design, either 3-d of high-CHO (11 g x kg(-1)d(-1) CHO, 1 g x kg(-1) x d(-1) fat HICHO) or an isoenergetic high-fat (2.6 g CHO x kg(-1) x d(-1), 4.6 g FAT x kg(-1) x d(-1) HIFAT) diet separated by an 18-d wash out. On the 1st (d-1) and 4th (d-4) day of each treatment, subjects completed a standardized laboratory training session consisting of a 20-min warm-up at 65% of VO2peak (232 +/- 23W) immediately followed by 8 x 5 min work bouts at 86 +/- 2% of VO2peak (323 +/- 32 W) with 60-s recovery. Respiratory exchange ratio (mean for bouts 1, 4, and 8) was similar on d-1 for HIFAT and HICHO (0.91 +/- 0.04 vs 0.92 +/- 0.03) and on d-4 after HICHO (0.92 +/- 0.03) but fell to 0.85 +/- 0.03 (P < 0.05) on d-4 after HIFAT. Accordingly, the rate of fat oxidation increased from 31 +/- 13 on d-1 to 61 +/- 25 micromol x kg(-1) x min(-1) on d-4 after HIFAT (P < 0.05). Blood lactate concentration was similar on d-1 and d-4 of HICHO and on d-1 of HIFAT (3.5 +/- 0.9 and 3.2 +/- 1.0 vs 3.7 +/- 1.2 mM) but declined to 2.4 +/- 0.5 mM on d-4 after HIFAT (P < 0.05). Ratings of perception of effort (legs) were similar on d-1 for HIFAT and HICHO (14.8 +/- 1.5 vs 14.1 +/- 1.4) and on d-4 after HICHO (13.8 +/- 1.8) but increased to 16.0 +/- 1.3 on d-4 after HIFAT (P < 0.05). 1) competitive endurance athletes can perform intense interval training during 3-d exposure to a high-fat diet, 2) such exercise elicited high rates of fat oxidation, but 3) compared with a high-carbohydrate diet, training sessions were associated with increased ratings of perceived exertion.
Publisher: American Diabetes Association
Date: 10-2006
DOI: 10.2337/DB05-1404
Abstract: Although interleukin-6 (IL-6) has been associated with insulin resistance, little is known regarding the effects of IL-6 on insulin sensitivity in humans in vivo. Here, we show that IL-6 infusion increases glucose disposal without affecting the complete suppression of endogenous glucose production during a hyperinsulinemic-euglycemic cl in healthy humans. Because skeletal muscle accounts for most of the insulin-stimulated glucose disposal in vivo, we examined the mechanism(s) by which IL-6 may affect muscle metabolism using L6 myotubes. IL-6 treatment increased fatty acid oxidation, basal and insulin-stimulated glucose uptake, and translocation of GLUT4 to the plasma membrane. Furthermore, IL-6 rapidly and markedly increased AMP-activated protein kinase (AMPK). To determine whether the activation of AMPK mediated cellular metabolic events, we conducted experiments using L6 myotubes infected with dominant-negative AMPK α-subunit. The effects described above were abrogated in AMPK dominant-negative–infected cells. Our results demonstrate that acute IL-6 treatment enhances insulin-stimulated glucose disposal in humans in vivo, while the effects of IL-6 on glucose and fatty acid metabolism in vitro appear to be mediated by AMPK.
Publisher: American Association for the Advancement of Science (AAAS)
Date: 11-10-2017
DOI: 10.1126/SCITRANSLMED.AAM6084
Abstract: Protecting the heart after an acute coronary syndrome is a key therapeutic goal to support cardiac recovery and prevent progression to heart failure. A potential strategy is to target cardiac glucose metabolism at the early stages after ischemia when glycolysis is critical for myocyte survival. Building on our discovery that high-density lipoprotein (HDL) modulates skeletal muscle glucose metabolism, we now demonstrate that a single dose of reconstituted HDL (rHDL) delivered after myocardial ischemia increases cardiac glucose uptake, reduces infarct size, and improves cardiac remodeling in association with enhanced functional recovery in mice. These findings applied equally to metabolically normal and insulin-resistant mice. We further establish direct effects of HDL on cardiomyocyte glucose uptake, glycolysis, and glucose oxidation via the Akt signaling pathway within 15 min of reperfusion. These data support the use of infusible HDL preparations for management of acute coronary syndromes in the setting of primary percutaneous interventions.
Publisher: Springer Science and Business Media LLC
Date: 08-12-2017
DOI: 10.1007/S00125-017-4514-X
Abstract: The baseline insulin data given in Table 1 for the placebo group were incorrectly reported as 51 ± 10 pmol/l instead of 48 ± 10 pmol/l. This mistake also impacts on data reported in Table 4.
Publisher: Wiley
Date: 03-10-2005
Abstract: There are multiple binding domains on the promoter region of the peroxisome proliferator activator receptor gamma coactivator-1 alpha (PGC-1alpha) gene, including a trio of insulin responsive elements that are activated by the forkhead box class-O (FoxO1) winged helix transcription factor, which is known to be regulated by acute transforming retrovirus thymoma (Akt). Here we show that in skeletal muscle biopsy specimens from healthy humans and cultured human skeletal myotubes, insulin phosphorylates Akt (Ser473) and FoxO1 (Thr24, Ser256), leading to reduced nuclear abundance of FoxO1 total protein. This is associated with an insulin-mediated repression of the mRNA expression PGC-1alpha and downstream genes associated with oxidative phosphorylation. In contrast, in muscle taken from insulin resistant humans or in palmitate-treated insulin resistant myotubes, neither Akt nor FoxO1 was phosphorylated by insulin, resulting in a failure for nuclear exclusion of FoxO1 total protein, and an inability for insulin to repress the mRNA expression of PGC-1alpha and down-stream genes. To determine whether the regulation of FoxO1 was Akt dependent, we next treated Akt2 -/- and wild-type mice with or without insulin. Insulin phosphorylated Akt and FoxO1 (Thr24, Ser256) resulting in a reduced nuclear expression of FoxO1 total protein in wild-type but not Akt2 -/- skeletal muscle. We conclude that insulin decreases the expression of genes involved in oxidative metabolism in healthy but not insulin resistant muscle, due to a decrease in FoxO1 phosphorylation and nuclear exclusion secondary to reduced Akt activity.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 03-2009
Publisher: Springer Science and Business Media LLC
Date: 30-11-2017
DOI: 10.1038/IJO.2017.295
Abstract: The phenomenon of adipocyte 'beiging' involves the conversion of non-classic brown adipocytes to brown-like adipose tissue with thermogenic, fat-burning properties, and this phenomenon has been shown in rodents to slow the progression of obesity-associated metabolic diseases. Rodent studies consistently report adipocyte beiging after endurance exercise training, indicating that increased thermogenic capacity in these adipocytes may underpin the improved health benefits of exercise training. The aim of this study was to determine whether prolonged endurance exercise training induces beige adipogenesis in subcutaneous adipose tissues of obese men. Molecular markers of beiging were examined in adipocytes obtained from abdominal subcutaneous (AbSC) and gluteofemoral (GF) subcutaneous adipose tissues before and after 6 weeks of endurance exercise training in obese men (n=6, 37.3±2.3 years, 30.1±2.3 kg m The mRNAs encoding the brown or beige adipocyte-selective proteins were very lowly expressed in AbSC and GF adipose tissues and exercise training did not alter the mRNA expression of UCP1, CD137, CITED, TBX1, LHX8 and TCF21. Using immunohistochemistry, neither multilocular adipocytes, nor UCP1 or CD137-positive adipocytes were detected in any s le. MicroRNAs known to regulate brown and/or beige adipose development were highly expressed in white adipocytes but endurance exercise training did not impact their expression. The present study reaffirms emerging data in humans demonstrating no evidence of white adipose tissue beiging in response to exercise training, and supports a growing body of work demonstrating ergence of brown/beige adipose location, molecular characterization and physiological function between rodents and humans.
Publisher: Elsevier BV
Date: 03-2003
DOI: 10.1016/S0006-291X(03)00267-5
Abstract: IL-6 expression in skeletal muscle is stimulated by contractions. We sought to examine whether hyperinsulinaemia increases IL-6 mRNA in skeletal muscle and whether any increase is modified in insulin resistant muscle. We hypothesized that intramuscular IL-6 mRNA would be increased in response to insulin, but such an affect would be unaffected by insulin resistance because the primary insulin sensitive signalling protein responsible for activating IL-6 functions normally in insulin resistant muscle. Transgenic rats over-expressing the gluconeogenic regulatory enzyme phosphoenolpyruvate carboxykinase (PEPCK) were studied. White gastrocnemius muscle s les were obtained under hyperinsulinaemic, euglycaemic cl (4 mU kg(-1)min(-1) insulin, plasma glucose concentration 4-6 mmol L(-1)) and basal conditions in both PEPCK (basal n=4 insulin n=5) and wild-type (CON) (basal n=5 insulin n=4) rats, which were previously injected with a bolus of 2-[1-14C]deoxyglucose (2-DG) into the carotid artery. Muscle s les were assayed for 2-DG uptake and IL-6 mRNA. No differences in 2-DG uptake or IL-6 mRNA were observed when comparing groups under basal conditions. Under cl conditions, 2-DG uptake was lower (P<0.05) in PEPCK compared with CON. Insulin stimulation in CON did not change IL-6 mRNA compared with basal levels. In contrast, there was an approximately 8-fold increase (P<0.05) in IL-6 mRNA in insulin-stimulated PEPCK compared with CON basal levels. Insulin stimulation increases IL-6 gene expression in insulin resistant, but not healthy, skeletal muscle, suggesting that IL-6 expression in skeletal muscle is sensitive to changes in insulin in circumstances of insulin resistance. It is likely that the differences observed when comparing healthy with insulin resistant muscle are due to the differential activation of insulin sensitive signalling proteins responsible for activating IL-6.
Publisher: Elsevier BV
Date: 12-2018
DOI: 10.1016/J.PHARMTHERA.2018.07.002
Abstract: Development of therapeutic agents directed towards increasing brown adipose tissue (BAT) energy expenditure to combat obesity and its comorbidities is currently an area of intense research. Both preclinical and clinical studies have suggested a potentially significant role for BAT in regulating whole body energy expenditure as well as glucose and lipid metabolism. Lipids, particularly long chain fatty acids (LCFAs), are recognized as integral substrates in mediating the primary heat-producing functions of BAT, and to date thought to be principally sourced from stored intracellular lipid droplets. While this prior understanding is not disputed, recent evidence has demonstrated the importance of lipids derived from the circulation, including those from dietary sources and from tissue lipolysis, especially white adipose tissue lipolysis. Moreover, recent studies have shed further light on a potential role for BAT as an autocrine, paracrine and endocrine organ, with lipids as key signaling molecules. Advances in metabolomics have enabled high-resolution exploration of biomolecules that may be associated with various physiological processes and potentially pathological states. Such approaches have led to several novel lipid species recently being associated with BAT function and dysfunction. Further exploration of the circulating lipidome will likely reveal additional novel BAT biomarkers that can inform development of BAT-directed therapies. This review will address current progress and new strategies to identify and characterize BAT-associated lipids which may represent both novel activators and/or activity biomarkers with both research and clinical utility.
Publisher: Elsevier BV
Date: 11-2004
DOI: 10.1016/J.METABOL.2004.05.015
Abstract: It has been hypothesized that epinephrine may stimulate interleukin (IL)-6 gene expression in skeletal muscle. The aim of the present study was to examine the effect of epinephrine on IL-6 gene expression within, and protein release from, skeletal muscle. We hypothesized that physiologic epinephrine would neither result in an increase in IL-6 mRNA nor protein release from skeletal muscle. Soleus muscle was excised from 4-week-old anesthetized Sprague Dawley rats and incubated in a Krebs buffer with the addition of either saline (CON), epinephrine, at concentrations of 1,000 nmol/L (EPI 1,000), 100 nmol/L (EPI 100), or 10 nmol/L (EPI 10), or the calcium ionophore, ionomycin (IONO), a positive control. After a 1-hour incubation, muscle was collected and extracted for RNA, reverse transcribed, and IL-6 gene expression was determined by real-time polymerase chain reaction (PCR). An aliquot of incubation medium was also collected and analyzed for IL-6 protein by enzyme-linked immunosorbent (ELISA). EPI 1,000 and IONO increased (P < .05) IL-6 mRNA, whereas EPI 100 and EPI 10 were without effect. IL-6 protein release from skeletal muscle was increased in IONO (P < .05), but not in CON or EPI at any concentration. These data demonstrate that while pharmacologic concentrations of epinephrine activate IL-6 mRNA, supraphysiologic and high-physiologic doses appear to have little, if any, effect on IL-6 gene transcription in skeletal muscle. In addition, ionomycin can stimulate IL-6 gene expression and protein release after only 1 hour of exposure.
Publisher: Springer Science and Business Media LLC
Date: 18-12-2004
DOI: 10.1007/S00125-004-1598-X
Abstract: Type 2 diabetes mellitus is characterised by increased plasma NEFA and IL-6 concentrations, and IL-6 increases lipolysis in healthy men. We assessed the adipose tissue hormone-sensitive lipase (HSL) mRNA expression, protein expression and HSL activity in patients with type 2 diabetes mellitus, and determined the effect of IL-6 administration on these measures. Seven patients with type 2 diabetes mellitus (age 67+/-4 years, weight 87+/-7 kg) and six age- and weight-matched in iduals visited the laboratory on two occasions. Subcutaneous adipose tissue biopsies and blood s les were obtained prior to and during 3 h of either saline or recombinant human IL-6 infusion. HSL mRNA was reduced (p<0.05) by approximately 40% in type 2 diabetes mellitus relative to control subjects, while HSL protein expression showed a tendency to be decreased (35%, p=0.09). HSL activity averaged 8.87+/-1.25 and 6.91+/-1.20 nmol min(-1) mg(-1) protein for control and type 2 diabetic subjects respectively (p<0.05). IL-6 administration increased (p<0.05) HSL mRNA 2-fold at 60 min in both groups, whereas HSL protein and activity were unaffected by IL-6. Plasma insulin was elevated (p<0.05) in patients with type 2 diabetes mellitus at rest and was blunted (p<0.05) during IL-6 infusion in both groups. Plasma glucagon and cortisol were elevated (p<0.05) by IL-6 in both groups. Our data demonstrate that basal HSL is decreased in patients with type 2 diabetes mellitus, and this may be a consequence of elevated plasma insulin levels. We have also shown that IL-6 administration increases HSL gene expression, although it exerted no effect on HSL protein and activity. This disparity between mRNA, protein and enzyme activity may be a function either of the marked alterations in the hormonal milieu induced by IL-6 administration and/or of post-transcriptional events.
Publisher: American Diabetes Association
Date: 09-2003
DOI: 10.2337/DIABETES.52.9.2338
Abstract: To examine whether genes associated with cellular defense against oxidative stress are associated with insulin sensitivity, patients with type 2 diabetes (n = 7) and age-matched (n = 5) and young (n = 9) control subjects underwent a euglycemic-hyperinsulinemic cl for 120 min. Muscle s les were obtained before and after the cl and analyzed for heat shock protein (HSP)72 and heme oxygenase (HO)-1 mRNA, intramuscular triglyceride content, and the maximal activities of β-hyroxyacyl-CoA dehydrogenase (β-HAD) and citrate synthase (CS). Basal expression of both HSP72 and HO-1 mRNA were lower (P & 0.05) by 33 and 55%, respectively, when comparing diabetic patients with age-matched and young control subjects, with no differences between the latter groups. Both basal HSP72 (r = 0.75, P & 0.001) and HO-1 (r = 0.50, P & 0.05) mRNA expression correlated with the glucose infusion rate during the cl . Significant correlations were also observed between HSP72 mRNA and both β-HAD (r = 0.61, P & 0.01) and CS (r = 0.65, P & 0.01). HSP72 mRNA was induced (P & 0.05) by the cl in all groups. Although HO-1 mRNA was unaffected by the cl in both the young and age-matched control subjects, it was increased (P & 0.05) ∼70-fold in the diabetic patients after the cl . These data demonstrate that genes involved in providing cellular protection against oxidative stress are defective in patients with type 2 diabetes and correlate with insulin-stimulated glucose disposal and markers of muscle oxidative capacity. The data provide new evidence that the pathogenesis of type 2 diabetes involves perturbations to the antioxidant defense mechanism within skeletal muscle.
Publisher: Springer Science and Business Media LLC
Date: 07-03-2019
DOI: 10.1038/S41598-019-40490-0
Abstract: Active breaks in prolonged sitting has beneficial impacts on cardiometabolic risk biomarkers. The molecular mechanisms include regulation of skeletal muscle gene and protein expression controlling metabolic, inflammatory and cell development pathways. An active communication network exists between adipose and muscle tissue, but the effect of active breaks in prolonged sitting on adipose tissue have not been investigated. This study characterized the acute transcriptional events induced in adipose tissue by regular active breaks during prolonged sitting. We studied 8 overweight/obese adults participating in an acute randomized three-intervention crossover trial. Interventions were performed in the postprandial state and included: (i) prolonged uninterrupted sitting or prolonged sitting interrupted with 2-minute bouts of (ii) light- or (iii) moderate-intensity treadmill walking every 20 minutes. Subcutaneous adipose tissue biopsies were obtained after each condition. Microarrays identified 36 differentially expressed genes between the three conditions (fold change ≥0.5 in either direction p 0.05). Pathway analysis indicated that breaking up of prolonged sitting led to differential regulation of adipose tissue metabolic networks and inflammatory pathways, increased insulin signaling, modulation of adipocyte cell cycle, and facilitated cross-talk between adipose tissue and other organs. This study provides preliminary insight into the adipose tissue regulatory systems that may contribute to the physiological effects of interrupting prolonged sitting.
Publisher: Elsevier BV
Date: 03-2011
DOI: 10.1016/J.MCE.2011.01.008
Abstract: The protein deacetylase SIRT1, and its activator resveratrol, exert beneficial effects on glucose metabolism. Different SIRT1 targets have been identified, including PTP1B, AMPK, FOXO, PGC-1α and IRS2. The latter may underscore a tight link between SIRT1 and insulin signaling components. However, whether SIRT1 has a direct effect on insulin resistance and whether resveratrol acts directly or indirectly in this context is still a matter of controversy and this question has not been addressed in muscle cells. Here, we show that SIRT1 protein expression is decreased in muscle biopsies and primary myotubes derived from type 2 diabetic patients, suggesting a contribution of diminished SIRT1 in the determination of muscle insulin resistance. To investigate the functional impact of SIRT1 on the insulin pathway, the activation of insulin downstream effector PKB was evaluated after SIRT1 inactivation by RNAi, SIRT1 overexpression, or resveratrol treatments. In muscle cells and HEK293 cells, downregulation of SIRT1 reduced, while overexpression increased, insulin-induced PKB activatory phosphorylation. Further molecular characterisation revealed that SIRT1 interacts in an insulin-independent manner with the PI3K adapter subunit p85. We then investigated whether resveratrol may improve insulin signaling in muscle cells via SIRT1, or alternative targets. Incubation of muscle cells with resveratrol reverted the insulin-resistant state induced by prolonged TNFα or insulin treatment. Resveratrol-dependent improvement of insulin-resistance occurred through inhibition of serine phosphorylation of IRS1/2, implicating resveratrol as a serine kinase inhibitor. Finally, a functional interaction between PI3K and SIRT1 was demonstrated in C. elegans, where constitutively active PI3K - mimicking increased IIS signaling - lead to shortened lifespan, while removal of sir-2.1 abolished PI3K-induced lifespan shortening. Our data identify SIRT1 as a positive modulator of insulin signaling in muscle cells through PI3K, and this mechanism appears to be conserved from C. elegans through humans.
Publisher: Springer Science and Business Media LLC
Date: 02-2015
DOI: 10.1038/NM.3797
Publisher: Elsevier BV
Date: 10-2003
DOI: 10.1016/J.BBRC.2003.09.048
Abstract: Interleukin-6 (IL-6) is a cytokine with immuno-regulatory functions. However, contracting skeletal muscle expresses and subsequently releases IL-6 in high amounts, and recent evidence in IL-6 deficient mice suggests a role of IL-6 in metabolism. Since IL-6 mRNA levels also increase in abdominal adipose tissue in response to exercise, we wanted to examine the possible existence of a positive feedback mechanism between muscle and adipose tissue. We obtained biopsies from human skeletal muscle and abdominal subcutaneous adipose tissue in relation to either 3h of bicycle exercise or recombinant human IL-6 infusion (rhIL-6) or saline infusion. In muscle, IL-6 mRNA increased (p<0.05) immediately after exercise, peaking at this time-point, whereas IL-6 mRNA in adipose tissue increased 1.5-h post exercise (p<0.05) displaying a different kinetic of induction. During rhIL-6 infusion, IL-6 mRNA increased 120-fold in muscle (p<0.05). In conclusion, the present study demonstrates that muscle IL-6 is regulated by an autocrine mechanism at the transcriptional level.
Publisher: Bioscientifica
Date: 03-06-2008
DOI: 10.1677/JOE-08-0113
Abstract: Chronic elevations in interleukin (IL)-6 have been associated with insulin resistance, but acute IL-6 administration can enhance insulin sensitivity. Our aim was to exogenously administer IL-6 to rats to elicit either chronic or repeated acute elevations in systemic IL-6. We hypothesized that a continuous elevation of IL-6 would inhibit glucose tolerance and insulin sensitivity while acute intermittent elevations would improve it. Male Wistar rats were treated for 14d with recombinant human IL-6 (2.4 μg/day) or saline administered either by miniosmotic pump (continuous IL-6) or via twice-daily injection (intermittent IL-6). Glucose and insulin tolerance tests were performed following 14-d treatment and 24 h later rats were administered a bolus of insulin (150 mU/g) or saline intraperitoneally. Approximately, 10 min after insulin injection soleus, gastrocnemius and liver were excised and rapidly frozen in liquid nitrogen for subsequent metabolic measures. Irrespective of the mode of delivery, IL-6 treatment increased basal insulin sensitivity, as measured by the homeostatic model assessment of insulin resistance, and enhanced glucose clearance during an i.p. glucose tolerance test. IL-6 increased circulating fatty acids, but did not increase triglyceride accumulation in either skeletal muscle or liver, while it increased the protein expression of both PPARα and UCP2 in skeletal muscle, suggesting that IL-6 can enhance fat oxidation via mitochondrial uncoupling. These data demonstrate that, irrespective of the mode of delivery, IL-6 administration over 2 weeks enhances glucose tolerance. Our results do not support the notion that prolonged chronically elevated IL-6 impairs insulin action in vivo .
Publisher: Springer Science and Business Media LLC
Date: 13-10-2012
DOI: 10.1007/S00125-012-2748-1
Abstract: Brown adipose tissue (BAT) activation increases energy consumption and may help in the treatment of obesity. Cold exposure is the main physiological stimulus for BAT thermogenesis and the sympathetic nervous system, which innervates BAT, is essential in this process. However, cold-induced BAT activation is impaired in obese humans. To explore the therapeutic potential of BAT, it is essential to determine whether pharmacological agents can activate BAT. We aimed to determine whether BAT can be activated in lean and obese humans after acute administration of an orally bioavailable sympathomimetic. In a randomised, double-blinded, crossover trial, we administered 2.5 mg/kg of oral ephedrine to nine lean (BMI 22 ± 1 kg/m²) and nine obese (BMI 36 ± 1 kg/m²) young men. On a separate day, a placebo was administered to the same participants. BAT activity was assessed by measuring glucose uptake with [¹⁸F]fluorodeoxyglucose and positron emission tomography-computed tomography imaging. BAT activity was increased by ephedrine compared with placebo in the lean, but unchanged in the obese, participants. The change in BAT activity after ephedrine compared with placebo was negatively correlated with various indices of body fatness. BAT can be activated via acute, oral administration of the sympathomimetic ephedrine in lean, but not in obese humans.
Publisher: Elsevier BV
Date: 12-2006
DOI: 10.1016/J.CMET.2006.11.005
Abstract: Elevated levels of tumor necrosis factor (TNFalpha) are implicated in the development of insulin resistance, but the mechanisms mediating these chronic effects are not completely understood. We demonstrate that TNFalpha signaling through TNF receptor (TNFR) 1 suppresses AMPK activity via transcriptional upregulation of protein phosphatase 2C (PP2C). This in turn reduces ACC phosphorylation, suppressing fatty-acid oxidation, increasing intramuscular diacylglycerol accumulation, and causing insulin resistance in skeletal muscle, effects observed both in vitro and in vivo. Importantly even at pathologically elevated levels of TNFalpha observed in obesity, the suppressive effects of TNFalpha on AMPK signaling are reversed in mice null for both TNFR1 and 2 or following treatment with a TNFalpha neutralizing antibody. Our data demonstrate that AMPK is an important TNFalpha signaling target and is a contributing factor to the suppression of fatty-acid oxidation and the development of lipid-induced insulin resistance in obesity.
Publisher: Public Library of Science (PLoS)
Date: 08-01-2014
Publisher: Springer Science and Business Media LLC
Date: 18-09-2008
DOI: 10.1007/S00394-008-0739-2
Abstract: Oxidative stress-induced reactive oxygen species are associated with the clinical manifestation of insulin resistance. Evidence suggests that antioxidant treatment may reduce this incidence. This study determined whether glucose oxidase (GO)-induced insulin resistance in cultured skeletal muscle cells could be ameliorated by pre-treatment with gamma-tocopherol (GT). Insulin sensitivity in L6 myotubes was assessed by 2-deoxy-D: -[(3)H]-glucose uptake. The phosphorylation of distal insulin signaling proteins Akt and the Akt substrate AS160 were determined by western blot. One hour treatment with 100 mU/ml GO decreased insulin-stimulated glucose uptake (P < 0.001). Pre-treatment with GT either partially (100 microM) or completely (200 microM) restored insulin-stimulated glucose uptake in cells after GO-induced insulin resistance. GO-induced oxidative stress did not impair insulin stimulated phosphorylation of Akt or AS160, but 200 microM GT increased insulin-stimulated phosphorylation of these key signaling proteins (P < 0.05). High-dose (200 microM) GT treatment ameliorated oxidative stress-induced insulin resistance in cultured rat L6 skeletal muscle cells.
Publisher: American Physiological Society
Date: 11-2008
DOI: 10.1152/JAPPLPHYSIOL.90882.2008
Abstract: We determined the effects of a cycle training program in which selected sessions were performed with low muscle glycogen content on training capacity and subsequent endurance performance, whole body substrate oxidation during submaximal exercise, and several mitochondrial enzymes and signaling proteins with putative roles in promoting training adaptation. Seven endurance-trained cyclists/triathletes trained daily (High) alternating between 100-min steady-state aerobic rides (AT) one day, followed by a high-intensity interval training session (HIT 8 × 5 min at maximum self-selected effort) the next day. Another seven subjects trained twice every second day (Low), first undertaking AT, then 1–2 h later, the HIT. These training schedules were maintained for 3 wk. Forty-eight hours before and after the first and last training sessions, all subjects completed a 60-min steady-state ride (60SS) followed by a 60-min performance trial. Muscle biopsies were taken before and after 60SS, and rates of substrate oxidation were determined throughout this ride. Resting muscle glycogen concentration (412 ± 51 vs. 577 ± 34 μmol/g dry wt), rates of whole body fat oxidation during 60SS (1,261 ± 247 vs. 1,698 ± 174 μmol·kg −1 ·60 min −1 ), the maximal activities of citrate synthase (45 ± 2 vs. 54 ± 1 mmol·kg dry wt −1 ·min −1 ), and β-hydroxyacyl-CoA-dehydrogenase (18 ± 2 vs. 23 ± 2 mmol·kg dry wt −1 ·min −1 ) along with the total protein content of cytochrome c oxidase subunit IV were increased only in Low (all P 0.05). Mitochondrial DNA content and peroxisome proliferator-activated receptor-γ coactivator-1α protein levels were unchanged in both groups after training. Cycling performance improved by ∼10% in both Low and High. We conclude that compared with training daily, training twice every second day compromised high-intensity training capacity. While selected markers of training adaptation were enhanced with twice a day training, the performance of a 1-h time trial undertaken after a 60-min steady-state ride was similar after once daily or twice every second day training programs.
Publisher: American Physiological Society
Date: 15-02-2013
DOI: 10.1152/JAPPLPHYSIOL.00978.2012
Abstract: Breaking up prolonged sitting has been beneficially associated with cardiometabolic risk markers in both observational and intervention studies. We aimed to define the acute transcriptional events induced in skeletal muscle by breaks in sedentary time. Overweight/obese adults participated in a randomized three-period, three-treatment crossover trial in an acute setting. The three 5-h interventions were performed in the postprandial state after a standardized test drink and included seated position with no activity and seated with 2-min bouts of light- or moderate-intensity treadmill walking every 20 min. Vastus lateralis biopsies were obtained in eight participants after each treatment, and gene expression was examined using microarrays validated with real-time quantitative PCR. There were 75 differentially expressed genes between the three conditions. Pathway analysis indicated the main biological functions affected were related to small-molecule biochemistry, cellular development, growth and proliferation, and carbohydrate metabolism. Interestingly, differentially expressed genes were also linked to cardiovascular disease. For ex le, relative to prolonged sitting, activity bouts increased expression of nicotamide N-methyltransferase, which modulates anti-inflammatory and anti-oxidative pathways and triglyceride metabolism. Activity bouts also altered expression of 10 genes involved in carbohydrate metabolism, including increased expression of dynein light chain, which may regulate translocation of the GLUT-4 glucose transporter. In addition, breaking up sedentary time reversed the effects of chronic inactivity on expression of some specific genes. This study provides insight into the muscle regulatory systems and molecular processes underlying the physiological benefits induced by interrupting prolonged sitting.
No related grants have been discovered for Andrew Carey.