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      Endurance Training-Induced Increase in Circulating Irisin Levels Is Associated with Reduction of Abdominal Visceral Fat in Middle-Aged and Older Adults

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          Abstract

          To elucidate the effects of endurance training on circulating irisin levels in young and middle-aged/older adults, and to determine the association between endurance training-induced alteration of irisin and reduction in body fat. Twenty-five healthy young (age 21 ± 1 years; 16 men, 9 women) and 28 healthy middle-aged/older adults (age 67 ± 8 years; 12 men, 16 women) participated in the study. Each age cohort was divided into two groups: the endurance-training group (14 young, 14 middle-aged/older) and the control group. Subjects in the training groups completed an 8-week endurance-training program (cycling at 60-70% peak oxygen uptake [

          O 2peak] for 45 min, 3 days/week). Before and after the intervention, we evaluated serum irisin level,
          O 2peak, and body composition. The increase in
          O 2peak in the young and middle-aged/older training groups after the intervention period was significantly greater than those in the young and middle-aged/older control groups ( P < 0.05). Serum irisin level was significantly increased in the middle-aged/older training group after the intervention period ( P < 0.01), but not in the young training group. Furthermore, in the middle-aged/older training group, the endurance training-induced reduction in visceral adipose tissue area was negatively correlated with the change in serum irisin level (r = −0.54, P < 0.05). These results suggest a possible role for secreted irisin in the exercise-induced alteration of abdominal visceral fat in middle-aged and older adults.

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          Age-predicted maximal heart rate revisited.

          We sought to determine a generalized equation for predicting maximal heart rate (HRmax) in healthy adults. The age-predicted HRmax equation (i.e., 220 - age) is commonly used as a basis for prescribing exercise programs, as a criterion for achieving maximal exertion and as a clinical guide during diagnostic exercise testing. Despite its importance and widespread use, the validity of the HRmax equation has never been established in a sample that included a sufficient number of older adults. First, a meta-analytic approach was used to collect group mean HRmax values from 351 studies involving 492 groups and 18,712 subjects. Subsequently, the new equation was cross-validated in a well-controlled, laboratory-based study in which HRmax was measured in 514 healthy subjects. In the meta-analysis, HRmax was strongly related to age (r = -0.90), using the equation of 208 - 0.7 x age. The regression equation obtained in the laboratory-based study (209 - 0.7 x age) was virtually identical to that obtained from the meta-analysis. The regression line was not different between men and women, nor was it influenced by wide variations in habitual physical activity levels. 1) A regression equation to predict HRmax is 208 - 0.7 x age in healthy adults. 2) HRmax is predicted, to a large extent, by age alone and is independent of gender and habitual physical activity status. Our findings suggest that the currently used equation underestimates HRmax in older adults. This would have the effect of underestimating the true level of physical stress imposed during exercise testing and the appropriate intensity of prescribed exercise programs.
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            Irisin is expressed and produced by human muscle and adipose tissue in association with obesity and insulin resistance.

            Recently irisin (encoded by Fndc5 gene) has been reported to stimulate browning and uncoupling protein 1 expression in sc adipose tissue of mice. The objective of the study was to investigate FNDC5 gene expression in human muscle and adipose tissue and circulating irisin according to obesity, insulin sensitivity, and type 2 diabetes. Adipose tissue FNDC5 gene expression and circulating irisin (ELISA) were analyzed in 2 different cohorts (n = 125 and n = 76); muscle FNDC5 expression was also evaluated in a subcohort of 34 subjects. In vitro studies in human preadipocytes and adipocytes and in induced browning of 3T3-L1 cells (by means of retinoblastoma 1 silencing) were also performed. In both sc and visceral adipose tissue, FNDC5 gene expression decreased significantly in association with obesity and was positively associated with brown adipose tissue markers, lipogenic, insulin pathway-related, mitochondrial, and alternative macrophage gene markers and negatively associated with LEP, TNFα, and FSP27 (a known repressor of brown genes). Circulating irisin and irisin levels in adipose tissue were significantly associated with FNDC5 gene expression in adipose tissue. In muscle, the FNDC5 gene was 200-fold more expressed than in adipose tissue, and its expression was associated with body mass index, PGC1α, and other mitochondrial genes. In obese participants, FNDC5 gene expression in muscle was significantly decreased in association with type 2 diabetes. Interestingly, muscle FNDC5 gene expression was significantly associated with FNDC5 and UCP1 gene expression in visceral adipose tissue. In men, circulating irisin levels were negatively associated with obesity and insulin resistance. Irisin was secreted from human adipocytes into the media, and the induction of browning in 3T3-L1 cells led to increased secreted irisin levels. Decreased circulating irisin concentration and FNDC5 gene expression in adipose tissue and muscle from obese and type 2 diabetic subjects suggests a loss of brown-like characteristics and a potential target for therapy.
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              FNDC5/Irisin Is Not Only a Myokine but Also an Adipokine

              Exercise provides clear beneficial effects for the prevention of numerous diseases. However, many of the molecular events responsible for the curative and protective role of exercise remain elusive. The recent discovery of FNDC5/irisin protein that is liberated by muscle tissue in response to exercise might be an important finding with regard to this unsolved mechanism. The most striking aspect of this myokine is its alleged capacity to drive brown-fat development of white fat and thermogenesis. However, the nature and secretion form of this new protein is controversial. The present study reveals that rat skeletal muscle secretes a 25 kDa form of FNDC5, while the 12 kDa/irisin theoretical peptide was not detected. More importantly, this study is the first to reveal that white adipose tissue (WAT) also secretes FNDC5; hence, it may also behave as an adipokine. Our data using rat adipose tissue explants secretomes proves that visceral adipose tissue (VAT), and especially subcutaneous adipose tissue (SAT), express and secrete FNDC5. We also show that short-term periods of endurance exercise training induced FNDC5 secretion by SAT and VAT. Moreover, we observed that WAT significantly reduced FNDC5 secretion in fasting animals. Interestingly, WAT of obese animals over-secreted this hormone, which might suggest a type of resistance. Because 72% of circulating FNDC5/irisin was previously attributed to muscle secretion, our findings suggest a muscle-adipose tissue crosstalk through a regulatory feedback mechanism.
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                Author and article information

                Contributors
                Role: Academic Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, CA USA )
                1932-6203
                20 March 2015
                2015
                : 10
                : 3
                : e0120354
                Affiliations
                [1 ]Faculty of Sport and Health Science, Ritsumeikan University, Shiga, Japan
                [2 ]Japan Society for the Promotion of Science, Tokyo, Japan
                Medical University Innsbruck, AUSTRIA
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                Conceived and designed the experiments: MI. Performed the experiments: EM K. Sato TK NH S. Fujie S. Fujita K. Sanada MI. Analyzed the data: EM NH S. Fujie MI. Contributed reagents/materials/analysis tools: EM TK TH IT MI. Wrote the paper: EM K. Sato TH IT MI.

                Article
                PONE-D-14-51115
                10.1371/journal.pone.0120354
                4368602
                25793753
                07c58ddb-741c-40c6-b94b-c1945178710e
                Copyright @ 2015

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited

                History
                : 13 November 2014
                : 7 February 2015
                Page count
                Figures: 3, Tables: 2, Pages: 12
                Funding
                This work was supported by Grants-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology of Japan (KAKENHI: #26282199 and #25560378, M. Iemitsu).
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                Research Article
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                All relevant data are within the paper.

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