Objective: This study aimed to examine the impact of high-fat-diet(HFD)-induced obesity on pain sensitivity and tetrahydrobiopterin (BH4) levels. The effect of moderate-intensity physical exercise, an anti-inflammatory non-pharmacological intervention, on pain scores was also investigated. Methods: Adult male C57BL/J6 mice were fed standard or an HFD for eight weeks. Their total body weight, food intake, locomotor and motivational behavior, and pain reflexes were measured. A subgroup of animals underwent physical exercise for five days per week over six weeks. Blood was collected for glucose tolerance testing and levels of lactate. Urine samples were collected to measure BH4 levels. Results: We showed that the HFD increased weight gain, epididymal white adipose tissue, and the percentage of body weight as epididymal fat. These anthropometric alterations were characterized by impaired glucose tolerance at four and eight weeks of the dietary intervention. It was also observed that reduced locomotor activity and higher pain scores in the HFD-fed mice were prevented by a physical exercise intervention. The HFD also induced an increase in urinary BH4 levels at four and eight weeks of intervention. Conclusions: The HFD increased scores of chemical and mechanical hyperalgesias, as well as urinary BH4 levels. Urinary BH4 can be proposed as a potential easy-to-access, sensitive, and reliable biomarker of pain development, and a promising target for the control of pain hypersensitivity in obesity.

Evidence has shown that caffeine administration reduces pro-inflammatory biomarkers, delaying fatigue and improving endurance performance. This study examined the effects of caffeine administration on the expression of inflammatory-, adenosine receptor- (the targets of caffeine), epigenetic-, and oxidative metabolism-linked genes in the vastus lateralis muscle of mice submitted to lipopolysaccharide (LPS)-induced inflammation. We showed that caffeine pre-treatment before LPS administration reduced the expression of Il1b, Il6, and Tnfa, and increased Il10 and Il13. The negative modulation of the inflammatory response induced by caffeine involved the reduction of inflammasome components, Asc and Casp1, promoting an anti-inflammatory scenario. Caffeine treatment per se promoted the upregulation of adenosinergic receptors, Adora1 and Adora2A, an effect that was counterbalanced by LPS. Moreover, there was observed a marked Adora2A promoter hypermethylation, which could represent a compensatory response towards the increased Adora2A expression. Though caffeine administration did not alter DNA methylation patterns, the expression of DNA demethylating enzymes, Tet1 and Tet2, was increased in mice receiving Caffeine+LPS, when compared with the basal condition. Finally, caffeine administration attenuated the LPS-induced catabolic state, by rescuing basal levels of Ampk expression. Altogether, the anti-inflammatory effects of caffeine in the muscle can be mediated by modifications on the epigenetic landscape.

1 Faculty of Sport Sciences and Physical Education, University of A Coruña, A Coruña, Spain, Department of Pedagogy, Faculty of Human Sciences, Medical School Hamburg, Hamburg, Germany, Department of Performance, Neuroscience, Therapy and Health, Faculty of Health Sciences, Medical School Hamburg, Hamburg, Germany, 4 School of Medicine, Anahuac Mayab University, Mérida, Mexico, Cognitive and Clinical Psychology Laboratory, Department of Human Science, European University of Rome, Rome, Italy, 6 Laboratório de Bioenergética e Estresse Oxidativo LABOX, Departamento de Bioquímica, Centro de Ciências Biológicas, Universidade Federal de Santa Catarina, Florianópolis, Brazil

Fatigue reflects a typical limitation of endurance to physical exertion, but it is also a symptom at rest in many neurodegenerative diseases, which impair common activities in patients with multiple sclerosis, Parkinson's disease, and Alzheimer's disease. In this case, the symptom is known as central fatigue. The pharmacological and environmental approach of central fatigue is not effective because the pathophysiology is unclear. Raised neuronal adenosine A2A receptor (A2AR) density is associated with the pathology and clinical condition of these neurodegenerative diseases. The nonselective adenosine receptor antagonist caffeine has been shown to be a good therapeutic option for these cases. Caffeine is also the main ergogenic resource used by athletes. In this mini-review, we propose that central fatigue can be mediated by A2AR in the central nervous system and that caffeine may be a good therapeutic option for central fatigue or neurodegenerative patients.

Obesity and metabolic disorders are increasing worldwide and are associated with brain atrophy and dysfunction, which are risk factors for late-onset dementia and Alzheimer's disease. Epidemiological studies demonstrated that changes in lifestyle, including the frequent practice of physical exercise are able to prevent and treat not only obesity/metabolic disorders, but also to improve cognitive function and dementia. Several biochemical pathways and epigenetic mechanisms have been proposed to understand the beneficial effects of physical exercise on cognition. This manuscript revised central ongoing research on epigenetic mechanisms induced by exercise and the beneficial effects on obesity-associated cognitive decline, highlighting potential mechanistic mediators.

Obesity and metabolic disorders are increasing worldwide and are associated with brain atrophy and dysfunction, which are risk factors for late-onset dementia and Alzheimer's disease. Epidemiological studies demonstrated that changes in lifestyle, including the frequent practice of physical exercise are able to prevent and treat not only obesity/metabolic disorders, but also to improve cognitive function and dementia. Several biochemical pathways and epigenetic mechanisms have been proposed to understand the beneficial effects of physical exercise on cognition. This manuscript revised central ongoing research on epigenetic mechanisms induced by exercise and the beneficial effects on obesity-associated cognitive decline, highlighting potential mechanistic mediators.

Received: February 12, 2017; Accepted: March 02, 2017; Published: March 06, 2017 Caffeine (1,3,7-trimethylxantine) is the most commonly consumed social drug in western society for increased physical and cognitive performance [1-5], and it is the main ergogenic resource used by athletes [6]. Initially controversial, caffeine was banned by the International Olympic Committee from 1980-2003 [1,6,7], but then in 2004 its use was approved by the World Anti-doping Agency (WADA), and later this year by the U.S. Anti-doping Agency (USADA; 2016). However, caffeine has remained on the lists of monitored substances of these anti-doping agencies.