ORCID Profile
0000-0002-5125-2190
Current Organisation
Aston University
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Publisher: American Diabetes Association
Date: 15-05-2014
DOI: 10.2337/DB13-0967
Abstract: Induction of heat shock protein (HSP)72 protects against obesity-induced insulin resistance, but the underlying mechanisms are unknown. Here, we show that HSP72 plays a pivotal role in increasing skeletal muscle mitochondrial number and oxidative metabolism. Mice overexpressing HSP72 in skeletal muscle (HSP72Tg) and control wild-type (WT) mice were fed either a chow or high-fat diet (HFD). Despite a similar energy intake when HSP72Tg mice were compared with WT mice, the HFD increased body weight, intramuscular lipid accumulation (triacylglycerol and diacylglycerol but not ceramide), and severe glucose intolerance in WT mice alone. Whole-body VO2, fatty acid oxidation, and endurance running capacity were markedly increased in HSP72Tg mice. Moreover, HSP72Tg mice exhibited an increase in mitochondrial number. In addition, the HSP72 coinducer BGP-15, currently in human clinical trials for type 2 diabetes, also increased mitochondrial number and insulin sensitivity in a rat model of type 2 diabetes. Together, these data identify a novel role for activation of HSP72 in skeletal muscle. Thus, the increased oxidative metabolism associated with activation of HSP72 has potential clinical implications not only for type 2 diabetes but also for other disorders where mitochondrial function is compromised.
Publisher: American Physiological Society
Date: 07-2020
DOI: 10.1152/AJPENDO.00037.2020
Abstract: Studies suggest the gut microbiota contributes to the development of obesity and metabolic syndrome. Exercise alters microbiota composition and ersity and is protective of these maladies. We tested whether the protective metabolic effects of exercise are mediated through fecal components through assessment of body composition and metabolism in recipients of fecal microbiota transplantation (FMT) from exercise-trained (ET) mice fed normal or high-energy diets. Donor C57BL/6J mice were fed a chow or high-fat, high-sucrose diet (HFHS) for 4 wk to induce obesity and glucose intolerance. Mice were ided into sedentary (Sed) or ET groups (6 wk treadmill-based ET) while maintaining their diets, resulting in four donor groups: chow sedentary (NC-Sed) or ET (NC-ET) and HFHS sedentary (HFHS-Sed) or ET (HFHS-ET). Chow-fed recipient mice were gavaged with feces from the respective donor groups weekly, creating four groups (NC-Sed-R, NC-ET-R, HFHS-Sed-R, HFHS-ET-R), and body composition and metabolism were assessed. The HFHS diet led to glucose intolerance and obesity in the donors, whereas exercise training (ET) restrained adiposity and improved glucose tolerance. No donor group FMT altered recipient body composition. Despite unaltered adiposity, glucose levels were disrupted when challenged in mice receiving feces from HFHS-fed donors, irrespective of donor-ET status, with a decrease in insulin-stimulated glucose clearance into white adipose tissue and large intestine and specific changes in the recipient’s microbiota composition observed. FMT can transmit HFHS-induced disrupted glucose metabolism to recipient mice independently of any change in adiposity. However, the protective metabolic effect of ET on glucose metabolism is not mediated through fecal factors.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 10-2007
Publisher: Wiley
Date: 03-05-2018
DOI: 10.1111/DOM.13319
Abstract: The induction of heat shock protein 72 (Hsp72) via heating, genetic manipulation or pharmacological activation is metabolically protective in the setting of obesity-induced insulin resistance across mammalian species. In this study, we set out to determine whether the overexpression of Hsp72, specifically in skeletal muscle, can protect against high-fat diet (HFD)-induced obesity and insulin resistance. An Adeno-Associated Viral vector (AAV), designed to overexpress Hsp72 in skeletal muscle only, was used to study the effects of increasing Hsp72 levels on various metabolic parameters. Two studies were conducted, the first with direct intramuscular (IM) injection of the AAV:Hsp72 into the tibialis anterior hind-limb muscle and the second with a systemic injection to enable body-wide skeletal muscle transduction. IM injection of the AAV:Hsp72 significantly improved skeletal muscle insulin-stimulated glucose clearance in treated hind-limb muscles, as compared with untreated muscles of the contralateral leg when mice were fed an HFD. Despite this finding, systemic administration of AAV:Hsp72 did not improve body composition parameters such as body weight, fat mass or percentage body fat, nor did it lead to an improvement in fasting glucose levels or glucose tolerance. Furthermore, no differences were observed for other metabolic parameters such as whole-body oxygen consumption, energy expenditure or physical activity levels. At the levels of Hsp72 over-expression reported herein, skeletal muscle-specific Hsp72 overexpression via IM injection has the capacity to increase insulin-stimulated glucose clearance in this muscle. However, upon systemic injection, which results in lower muscle Hsp72 overexpression, no beneficial effects on whole-body metabolism are observed.
Publisher: Wiley
Date: 27-03-2012
DOI: 10.1111/J.1537-2995.2012.03613.X
Abstract: The fear for adverse effects of blood donation on subsequent exercise may prevent physically active people from donating. We studied the impact of a standard blood bank donation (i.e., 450-mL blood withdrawal) on the thermoregulatory and cardiovascular responses to prolonged exercise in the heat. Eight moderately trained, heat-acclimated males cycled for 1 hour at 60% in a hot environment (34.9±0.6 °C) on four occasions: 1) 2 days before blood donation (CON), 2) 2 hours after donation (DON), 3) 2 days after donation (2 DAYS), and 4) 7 days after donation (7 DAYS). Two-thirds of the blood volume withdrawn was endogenously restored before exercise in the DON trial (p<0.05). DON started with increased preexercise rectal temperature (TRE 0.42±0.1 °C above CON p<0.05), which resulted in high levels of hyperthermia (i.e., 39.0±0.2 °C) after 1 hour of exercise. Skin temperature (34.5±0.1 °C) and sweat rate (1.15±0.1 L/h) were not affected by DON. However, DON lowered the skin blood flow:TRE relationship and elevated heart rate (HR) above CON (12±4 beats/min p<0.05) maintaining cardiac output. After 2 DAYS, TRE and HR were restored to CON levels while cardiac output increased above CON (6% p<0.05) in association with reduced hemoglobin concentration (i.e., peak hemodilution). A blood bank donation increases preexercise TRE. Subsequent exercise in a hot environment results in high levels of hyperthermia and HR. These thermoregulatory and cardiovascular perturbations observed during exercise disappear 2 days after donation.
Publisher: Elsevier BV
Date: 03-2015
DOI: 10.1016/J.CMET.2015.02.006
Abstract: Interleukin-6 (IL-6) plays a paradoxical role in inflammation and metabolism. The pro-inflammatory effects of IL-6 are mediated via IL-6 "trans-signaling," a process where the soluble form of the IL-6 receptor (sIL-6R) binds IL-6 and activates signaling in inflammatory cells that express the gp130 but not the IL-6 receptor. Here we show that trans-signaling recruits macrophages into adipose tissue (ATM). Moreover, blocking trans-signaling with soluble gp130Fc protein prevents high-fat diet (HFD)-induced ATM accumulation, but does not improve insulin action. Importantly, however, blockade of IL-6 trans-signaling, unlike complete ablation of IL-6 signaling, does not exacerbate obesity-induced weight gain, liver steatosis, or insulin resistance. Our data identify the sIL-6R as a critical chemotactic signal for ATM recruitment and suggest that selectively blocking IL-6 trans-signaling may be a more favorable treatment option for inflammatory diseases, compared with current treatments that completely block the action of IL-6 and negatively impact upon metabolic homeostasis.
Publisher: Springer Science and Business Media LLC
Date: 25-01-2015
Publisher: American Diabetes Association
Date: 15-08-2013
DOI: 10.2337/DB12-1095
Abstract: Circulating interleukin (IL)-18 is elevated in obesity, but paradoxically causes hypophagia. We hypothesized that IL-18 may attenuate high-fat diet (HFD)-induced insulin resistance by activating AMP-activated protein kinase (AMPK). We studied mice with a global deletion of the α-isoform of the IL-18 receptor (IL-18R−/−) fed a standard chow or HFD. We next performed gain-of-function experiments in skeletal muscle, in vitro, ex vivo, and in vivo. We show that IL-18 is implicated in metabolic homeostasis, inflammation, and insulin resistance via mechanisms involving the activation of AMPK in skeletal muscle. IL-18R−/− mice display increased weight gain, ectopic lipid deposition, inflammation, and reduced AMPK signaling in skeletal muscle. Treating myotubes or skeletal muscle strips with IL-18 activated AMPK and increased fat oxidation. Moreover, in vivo electroporation of IL-18 into skeletal muscle activated AMPK and concomitantly inhibited HFD-induced weight gain. In summary, IL-18 enhances AMPK signaling and lipid oxidation in skeletal muscle implicating IL-18 in metabolic homeostasis.
Publisher: Public Library of Science (PLoS)
Date: 06-11-2014
Publisher: Springer Science and Business Media LLC
Date: 25-09-2019
DOI: 10.1038/S41586-019-1601-9
Abstract: The gp130 receptor cytokines IL-6 and CNTF improve metabolic homeostasis but have limited therapeutic use for the treatment of type 2 diabetes. Accordingly, we engineered the gp130 ligand IC7Fc, in which one gp130-binding site is removed from IL-6 and replaced with the LIF-receptor-binding site from CNTF, fused with the Fc domain of immunoglobulin G, creating a cytokine with CNTF-like, but IL-6-receptor-dependent, signalling. Here we show that IC7Fc improves glucose tolerance and hyperglycaemia and prevents weight gain and liver steatosis in mice. In addition, IC7Fc either increases, or prevents the loss of, skeletal muscle mass by activation of the transcriptional regulator YAP1. In human-cell-based assays, and in non-human primates, IC7Fc treatment results in no signs of inflammation or immunogenicity. Thus, IC7Fc is a realistic next-generation biological agent for the treatment of type 2 diabetes and muscle atrophy, disorders that are currently pandemic.
Publisher: American Physiological Society
Date: 05-2015
DOI: 10.1152/AJPENDO.00547.2014
Abstract: The accumulation of lipid at ectopic sites, including the skeletal muscle and liver, is a common consequence of obesity and is associated with tissue-specific and whole body insulin resistance. Exercise is well known to improve insulin resistance by mechanisms not completely understood. We performed lipidomic profiling via mass spectrometry in liver and skeletal muscle s les from exercise-trained mice to decipher the lipid changes associated with exercise-induced improvements in whole body glucose metabolism. Obesity and insulin resistance were induced in C57BL/6J mice by high-fat feeding for 4 wk. Mice then underwent an exercise training program (treadmill running) 5 days/wk (Ex) for 4 wk or remained sedentary (Sed). Compared with Sed, Ex displayed improved ( P 0.01) whole body metabolism as measured via an oral glucose tolerance test. Deleterious lipid species such as diacylglycerol ( P 0.05) and cholesterol esters ( P 0.01) that accumulate with high-fat feeding were decreased in the liver of trained mice. Furthermore, the ratio of phosphatidylcholine (PC) to phosphatidylethanolamine (PE) (the PC/PE ratio), which is associated with membrane integrity and linked to hepatic disease progression, was increased by training ( P 0.05). These findings occurred without corresponding changes in the skeletal muscle lipidome. A concomitant decrease ( P 0.05) was observed for the fatty acid transporters CD36 and FATP4 in the liver, suggesting that exercise stimulates a coordinated reduction in fatty acid entry into hepatocytes. Given the important role of the liver in the regulation of whole body glucose homeostasis, hepatic lipid regression may be a key component by which exercise can improve metabolism.
Publisher: Wiley
Date: 09-2013
DOI: 10.1111/DOM.12170
Abstract: Obesity and type 2 diabetes are now the most prevalent metabolic diseases in the Western world and the development of new strategies to treat these metabolic diseases is most warranted. Obesity results in a state of chronic low-grade inflammation in metabolically active tissues such as the liver, adipose tissue, brain and skeletal muscle. Work in our laboratory has focussed on the role of the cytokine interleukin-6 (IL)-6 and other IL-6-like cytokines that signal through the gp130 receptor complex. We have focussed on the role of blocking IL-6 trans-signalling to prevent inflammation on the one hand, and activating membrane-bound signalling to promote insulin sensitivity on the other hand. Since the cloning of the IL-6 gene nearly 30 years ago, a pattern has emerged associating IL-6 with a number of diseases associated with inflammation including rheumatoid arthritis (RA), Crohn's disease and several cancers. Accordingly, tocilizumab, an IL-6 receptor-inhibiting monoclonal antibody, is now useful for the treatment of RA. However, this may not be the most optimal strategy to block inflammation associated with IL-6 and may result in unwanted side effects that, paradoxically, could actually promote metabolic disease.
Publisher: Wiley
Date: 05-03-2020
Publisher: Springer Science and Business Media LLC
Date: 26-07-2012
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 04-2008
Publisher: Elsevier BV
Date: 03-2016
Publisher: Springer Science and Business Media LLC
Date: 28-03-2010
DOI: 10.1007/S00421-010-1436-4
Abstract: To determine if the increases in rectal temperature (T(REC)) during exercise in the heat at a given percent of VO2peak depend on a subject's aerobic fitness level. On three occasions, 10 endurance-trained (Tr) and 10 untrained (UTr) subjects (VO2peak: 60 +/- 6 vs. 44 +/- 3 mL kg(-1) min(-1), P < 0.05) cycled in a hot-dry environment (36 +/- 1 degrees C 25 +/- 2% humidity, airflow 2.5 m s(-1)) at three workloads (40, 60, and 80% VO2peak). At the same percent of VO2peak, on average, Tr had 28 +/- 5% higher heat production but also higher skin blood flow (29 +/- 3%) and sweat rate (20 +/- 7% P = 0.07) and lower skin temperature (0.5 degrees C P < 0.05). Pre-exercise T(REC) was lower in the Tr subjects (37.4 +/- 0.2 vs. 37.6 +/- 0.2 P < 0.05) but similar to the UTr at the end of 40 and 60% VO2peak trials. Thus, exercise T(REC) increased more in the Tr group than in the UTr group (0.6 +/- 0.1 vs. 0.3 +/- 0.1 degrees C at 40% VO2peak and 1.0 +/- 0.1 vs. 0.6 +/- 0.3 degrees C at 60% VO2peak P < 0.05). At 80% VO2peak not only the increase in T(REC) (1.7 +/- 0.1 vs. 1.3 +/- 0.3 degrees C) but also the final T(REC) was larger in Tr than in UTr subjects (39.15 +/- 0.1 vs. 38.85 +/- 0.1 degrees C P < 0.05). During exercise in the heat at the same relative intensity, aerobically trained in iduals have a larger rise in T(REC) than do the untrained ones which renders them more hyperthermic after high-intensity exercise.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 2009
Publisher: Elsevier BV
Date: 2018
DOI: 10.1016/J.CMET.2017.12.001
Abstract: Exercise stimulates the release of molecules into the circulation, supporting the concept that inter-tissue signaling proteins are important mediators of adaptations to exercise. Recognizing that many circulating proteins are packaged in extracellular vesicles (EVs), we employed quantitative proteomic techniques to characterize the exercise-induced secretion of EV-contained proteins. Following a 1-hr bout of cycling exercise in healthy humans, we observed an increase in the circulation of over 300 proteins, with a notable enrichment of several classes of proteins that compose exosomes and small vesicles. Pulse-chase and intravital imaging experiments suggested EVs liberated by exercise have a propensity to localize in the liver and can transfer their protein cargo. Moreover, by employing arteriovenous balance studies across the contracting human limb, we identified several novel candidate myokines, released into circulation independently of classical secretion. These data identify a new paradigm by which tissue crosstalk during exercise can exert systemic biological effects.
Publisher: Public Library of Science (PLoS)
Date: 11-06-2012
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 11-2008
Publisher: Wiley
Date: 06-08-2015
DOI: 10.1002/OBY.21170
Abstract: Adipose inflammation and dysfunction underlie metabolic obesity. Exercise improves glycemic control and metabolic indices, but effects on adipose function and inflammation are less clear. Accordingly, it was hypothesized that exercise improves adipose morphometry to reduce adipose inflammation in hyperphagic obese mice. Alms1 mutant foz/foz mice housed in pairs were fed an atherogenic or chow diet half the cages were fitted with a computer-monitored wheel for voluntary exercise. Insulin-induced AKT-phosphorylation, adipocyte size distribution, and inflammatory recruitment were studied in visceral versus subcutaneous depots, and severity of fatty liver disease was determined. Exercise prevented obesity and diabetes development in chow-fed foz/foz mice and delayed their onset in atherogenic-fed counterparts. Insulin-stimulated phospho-AKT levels in muscle were improved with exercise, but not in adipose or liver. Exercise suppressed adipose inflammatory recruitment, particularly in visceral adipose, associated with an increased number of small adipocyte subpopulations, and enhanced expression of beige adipocyte factor PRDM16 in subcutaneous fat. In atherogenic-fed foz/foz mice liver, exercise suppressed development of nonalcoholic steatohepatitis and related liver fibrosis. Exercise confers metabo-protective effects in atherogenic-fed hyperphagic mice by preventing early onset of obesity and diabetes in association with enhanced muscle insulin sensitivity, improved adipose morphometry, and suppressed adipose and liver inflammation.
Publisher: Springer Science and Business Media LLC
Date: 30-03-2014
DOI: 10.1038/NI.2865
Publisher: Informa UK Limited
Date: 03-2011
Publisher: Informa UK Limited
Date: 09-2010
Publisher: Canadian Science Publishing
Date: 04-2008
DOI: 10.1139/H07-188
Abstract: The effects that rehydrating drinks ingested during exercise may have on anaerobic exercise performance are unclear. This study aimed to determine which of four commercial rehydrating drinks better maintains leg power and force during prolonged cycling in the heat. Seven endurance-trained and heat-acclimatized cyclists pedaled for 120 min at 63% maximum oxygen consumption in a hot, dry environment (36 °C 29% humidity, 1.9 m·s –1 airflow). In five randomized trials, during exercise, subjects drank 2.4 ± 0.1 L of (i) mineral water (WAT San Benedetto®), (ii) 6% carbohydrate–electrolyte solution (Gatorade® lemon), (iii) 8% carbohydrate–electrolyte solution (Powerade® Citrus Charge), (iv) 8% carbohydrate–electrolyte solution with lower sodium concentration than other sports drinks (Aquarius® orange), or (v) did not ingest any fluid (DEH). Fluid balance, rectal temperature (T rec ), maximal cycling power (P max ), and leg maximal voluntary isometric contraction (MVC) were measured. During DEH, subjects lost 3.7 ± 0.2% of initial body mass, whereas subjects lost only 0.8% ± 0.1% in the other trials (p 0.05). Final T rec was higher in DEH than in the rest of the trials (39.4 ± 0.1 °C vs. 38.7 ± 0.1 °C p 0.05). P max was similar among all trials. Gatorade® and Powerade® preserved MVC better than DEH (–3.1% ± 2% and –3.8% ± 2% vs. –11% ± 2%, p 0.05), respectively, whereas WAT and Aquarius® did not (–6% ± 2%). Compared with DEH, rehydration with commercially available sports drinks during prolonged exercise in the heat preserves leg force, whereas rehydrating with water does not. However, low sodium concentration in a sports drink seems to preclude its ergogenic effects on force.
Location: United Kingdom of Great Britain and Northern Ireland
No related grants have been discovered for Emma Estevez.