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      Role or Synergistic Interaction of Adenosine and Vitamin D3 Alongside High-Intensity Interval Training and Isocaloric Moderate Intensity Training on Metabolic Parameters: Protocol for an Experimental Study

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          Abstract

          Background

          Obesity is known as one of the major causes of epidemiologic diseases worldwide; therefore, the introduction of treatment strategies by medical professionals, such as the use of various medicines and exercise programs to reduce fat or prevent obesity, is on the rise. Recently, researchers have shown special interest in assessing the effect of lipolytic adenosine and vitamin D deficiency, as well as the effect of exercise, on decreasing body fat percentage.

          Objective

          This study has been designed to examine the effect of adenosine and vitamin D3 injections, in conjunction with high-intensity interval training and isocaloric moderate-intensity training, on the metabolic parameters of obesity induced by a high-fat diet.

          Methods

          This is an experimental study using 92 Wistar rats. At 6 weeks of age, the rats' weights will be recorded, after which they will have 1 week to adapt to their new environment before being divided into 12 groups. The rats will participate in a 2-stage experimental intervention, including a 13-week fattening diet phase followed by a 12-week exercise training phase consisting of an exercise program and the injection of adenosine and vitamin D3. Groups 1 and 2 will have a normal diet, and the other groups will have a diet of 40% fat, with free access to food and water up to the second half of the second stage of the study (end of the sixth week of training). After termination of the interventions, tissue collection and molecular assessments (blood for biochemical, tissues for gene expression analyses, and anthropometrical indexes) will be performed.

          Results

          The project was initiated in April 2017 and completed in December 2017. Data analysis is under way, and the first results are expected to be submitted for publication in November 2018.

          Conclusions

          We hypothesize that weight loss–induced molecular changes and upregulation will be observed in line with an increase in lipolysis and beta oxidation in muscle and fat tissue as a result of performing isocaloric training in drug-receiving rats and groups on a high-fat diet.

          International Registered Report Identifier (IRRID)

          RR1-10.2196/10753

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          Most cited references41

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          International Union of Basic and Clinical Pharmacology. LXXXI. Nomenclature and classification of adenosine receptors--an update.

          In the 10 years since our previous International Union of Basic and Clinical Pharmacology report on the nomenclature and classification of adenosine receptors, no developments have led to major changes in the recommendations. However, there have been so many other developments that an update is needed. The fact that the structure of one of the adenosine receptors has recently been solved has already led to new ways of in silico screening of ligands. The evidence that adenosine receptors can form homo- and heteromultimers has accumulated, but the functional significance of such complexes remains unclear. The availability of mice with genetic modification of all the adenosine receptors has led to a clarification of the functional roles of adenosine, and to excellent means to study the specificity of drugs. There are also interesting associations between disease and structural variants in one or more of the adenosine receptors. Several new selective agonists and antagonists have become available. They provide improved possibilities for receptor classification. There are also developments hinting at the usefulness of allosteric modulators. Many drugs targeting adenosine receptors are in clinical trials, but the established therapeutic use is still very limited.
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            Effect of diet and exercise, alone or combined, on weight and body composition in overweight-to-obese postmenopausal women.

            Lifestyle interventions for weight loss are the cornerstone of obesity therapy, yet their optimal design is debated. This is particularly true for postmenopausal women; a population with a high prevalence of obesity yet toward whom fewer studies are targeted. We conducted a year-long, 4-arm randomized trial among 439 overweight-to-obese postmenopausal sedentary women to determine the effects of a calorie-reduced, low-fat diet (D), a moderate-intensity, facility-based aerobic exercise program (E), or the combination of both interventions (D+E), vs. a no-lifestyle-change control (C) on change in body weight and composition. The group-based dietary intervention had a weight-reduction goal of ≥10%, and the exercise intervention consisted of a gradual escalation to 45-min aerobic exercise 5 day/week. Participants were predominantly non-Hispanic whites (85%) with a mean age of 58.0 ± 5.0 years, a mean BMI of 30.9 ± 4.0 kg/m(2) and an average of 47.8 ± 4.4% body fat. Baseline and 12-month weight and adiposity measures were obtained by staff blinded to participants' intervention assignment. Three hundred and ninety nine women completed the trial (91% retention). Using an intention-to-treat analysis, average weight loss at 12 months was -8.5% for the D group (P < 0.0001 vs. C), -2.4% for the E group (P = 0.03 vs. C), and -10.8% for the D+E group (P < 0.0001 vs. C), whereas the C group experienced a nonsignificant -0.8% decrease. BMI, waist circumference, and % body fat were also similarly reduced. Among postmenopausal women, lifestyle-change involving diet, exercise, or both combined over 1 year improves body weight and adiposity, with the greatest change arising from the combined intervention.
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              Adenosine activates brown adipose tissue and recruits beige adipocytes via A2A receptors.

              Brown adipose tissue (BAT) is specialized in energy expenditure, making it a potential target for anti-obesity therapies. Following exposure to cold, BAT is activated by the sympathetic nervous system with concomitant release of catecholamines and activation of β-adrenergic receptors. Because BAT therapies based on cold exposure or β-adrenergic agonists are clinically not feasible, alternative strategies must be explored. Purinergic co-transmission might be involved in sympathetic control of BAT and previous studies reported inhibitory effects of the purinergic transmitter adenosine in BAT from hamster or rat. However, the role of adenosine in human BAT is unknown. Here we show that adenosine activates human and murine brown adipocytes at low nanomolar concentrations. Adenosine is released in BAT during stimulation of sympathetic nerves as well as from brown adipocytes. The adenosine A2A receptor is the most abundant adenosine receptor in human and murine BAT. Pharmacological blockade or genetic loss of A2A receptors in mice causes a decrease in BAT-dependent thermogenesis, whereas treatment with A2A agonists significantly increases energy expenditure. Moreover, pharmacological stimulation of A2A receptors or injection of lentiviral vectors expressing the A2A receptor into white fat induces brown-like cells-so-called beige adipocytes. Importantly, mice fed a high-fat diet and treated with an A2A agonist are leaner with improved glucose tolerance. Taken together, our results demonstrate that adenosine-A2A signalling plays an unexpected physiological role in sympathetic BAT activation and protects mice from diet-induced obesity. Those findings reveal new possibilities for developing novel obesity therapies.
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                Author and article information

                Contributors
                Journal
                JMIR Res Protoc
                JMIR Res Protoc
                ResProt
                JMIR Research Protocols
                JMIR Publications (Toronto, Canada )
                1929-0748
                January 2019
                30 January 2019
                : 8
                : 1
                : e10753
                Affiliations
                [1 ] Department of Exercise Physiology Faculty of Physical Education and Sports Science Islamic Azad University, Central Tehran Branch Tehran Islamic Republic of Iran
                [2 ] Department of Exercise Physiology Islamic Azad University, Science and Research Branch Tehran Islamic Republic of Iran
                [3 ] Department of Physical Education and Sport Science Islamic Azad University, Karaj Branch Karaj Islamic Republic of Iran
                Author notes
                Corresponding Author: Seyed Javad Mirghani seyedgavadmirghani@ 123456yahoo.com
                Author information
                https://orcid.org/http://orcid.org/0000-0002-4846-3077
                https://orcid.org/http://orcid.org/0000-0003-1415-7319
                https://orcid.org/http://orcid.org/0000-0002-7331-0718
                https://orcid.org/http://orcid.org/0000-0002-5832-736X
                https://orcid.org/http://orcid.org/0000-0003-1847-9745
                https://orcid.org/http://orcid.org/0000-0002-9100-7149
                https://orcid.org/http://orcid.org/0000-0001-5985-9248
                https://orcid.org/http://orcid.org/0000-0002-1345-4461
                https://orcid.org/http://orcid.org/0000-0002-5681-3145
                https://orcid.org/http://orcid.org/0000-0002-3392-7692
                https://orcid.org/http://orcid.org/0000-0002-2603-2727
                https://orcid.org/http://orcid.org/0000-0002-8748-7557
                https://orcid.org/http://orcid.org/0000-0002-9034-3562
                https://orcid.org/http://orcid.org/0000-0002-3502-7487
                Article
                v8i1e10753
                10.2196/10753
                6372933
                30698527
                05f6b79d-5e79-427d-aff9-fbef770195e5
                ©Seyed Javad Mirghani, Maghsoud Peeri, Omid Yaghoobpour Yekani, Masoud Zamani, Foad Feizolahi, Sina Nikbin, Armin Derakhshideh, Niloufar Mousavi, Zohreh Khojasteh, Zeynab Nasrollahi, Elya Khorasani, Elham Ghodousi Johari, Tayebeh Afshar, Mohammad Ali Azarbayjani. Originally published in JMIR Research Protocols (http://www.researchprotocols.org), 30.01.2019.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License ( https://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work, first published in JMIR Research Protocols, is properly cited. The complete bibliographic information, a link to the original publication on http://www.researchprotocols.org.as well as this copyright and license information must be included.

                History
                : 11 April 2018
                : 7 June 2018
                : 8 September 2018
                : 10 September 2018
                Categories
                Protocol
                Protocol

                high-fat, diet-induced obesity,high-intensity interval training,isocaloric moderate-intensity training,vitamin d3,adenosine,metabolic parameters,weight loss

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