Introduction
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A physically inactive lifestyle is associated with the development of non-communicable diseases (NCD), such as cardiovascular diseases, type 2 diabetes, some cancers, and an overall increased mortality rate ([@B17]; [@B52]; [@B13]; [@B84]; [@B72]). Physical inactivity is also considered a risk factor for abdominal obesity, high serum triglyceride levels, low-density lipoprotein, cholesterol, hypertension, and hyperglycemia, which together characterize metabolic syndrome ([@B9]). Physical exercise has several benefits for physical and mental health ([@B4]; [@B37]; [@B30]; [@B59]), including increased physical and cardiorespiratory capacity (or fitness), improved body composition and balance (or fatness), and greater muscle strength and flexibility ([@B37]; [@B39]). Physical exercise also improves the serum lipid profile, decreases glucose intolerance, and attenuates insulin resistance ([@B57]; [@B19]; [@B76]). The literature supports the fitness-fatness hypothesis, which suggests that a higher level of cardiorespiratory fitness will reduce the adverse effects of obesity on morbidity and mortality, making obesity a much less important factor for health than is generally believed ([@B43]; [@B34]; [@B10]). The data are mixed, but for many authors, fitness is more important than fatness for early mortality ([@B14]; [@B97]; [@B66]; [@B10]). This is important for individuals who are unable to lose weight but are able to engage in a regular physical activity program.

The American College of Sports Medicine (ACSM) recommends increasing total energy expenditure (TEE; kcal/day) for health, with a minimum of 30 min of moderate physical exercise 5 days/week or 20 min of vigorous exercise 3 days/week ([@B44]). The ACSM also recommends combining moderate (3--6 MET) and vigorous activities (\>6 MET) ([@B44]). The [@B100] recommends that individuals participate in at least 150 or 75 min/week of moderate or vigorous physical activities, respectively. For overweight and obesity, the ACSM recommends increased physical activity, between 150 and 250 min/week to prevent weight gain or provide modest weight loss ([@B27]). Larger amounts of exercise (\>250 min/week) are needed for clinically significant weight loss ([@B27]). However, physical activity for weight loss is controversial; the amount of weight lost due to an exercise intervention is often less than what is predicted to be lost based on the exercise workload, suggesting a smaller increase in TEE (and smaller energy imbalance) than expected ([@B92]; [@B67]; [@B32]). This reduced energy imbalance occurs through metabolic and behavioral modifications in humans ([@B75]) and reinforces the hypothesis that fitness is more important than fatness for health. In general, the 150 min/week of moderate physical activity or 60--75 min/week of vigorous activity recommendations of ACSM and WHO is effective for overall health.

Even single exercise sessions, which increases the production of endogenous opioids ([@B39]), angiogenesis factors (such as vascular endothelial growth factor \[VEGF\], hypoxia-induced 1 alpha factor \[HIF-1α\] and erythropoietin \[EPO\]) ([@B79]) appear to be healthy, and they protect against hyperglycemia peaks ([@B54]) in humans. A single exercise session increases the plasma endocannabinoid levels in mice ([@B36]), which is a possible mechanism for the euphoric state (runner's high) that occurs after long runs ([@B16]).

The central nervous system (CNS) was the last physiological system approached by the exercise sciences. Lack of exercise is a major cause of chronic diseases ([@B17]), including brain diseases, such as depression ([@B31]; [@B3]), and neurodegenerative diseases ([@B77]; [@B105]; [@B2]). However, physical exercise is a neuroprotective agent against depression ([@B85]), anxiety disorders ([@B48]), cognitive decline/dementia in elderly people ([@B1]; [@B86]), Parkinson's disease ([@B20]), and Alzheimer's disease ([@B2]; [@B55]). Animal studies have shown that physical exercise increases neuronal survival, cerebral vascularization, neurogenesis, and mitochondrial metabolism, while it decreases the effects of neurotoxins on the CNS ([@B3]; [@B106]). Iris and uncoupling proteins (U) are candidate mechanisms for these exercise-induced changes.

In mammals, transcriptional peroxisome proliferator-activated receptor gamma (PPAR-γ) coactivator 1-alpha (PGC-1α)/fibronectin type III domain-containing protein 5 (FNDC5, the precursor of irisin), which is secreted during exercise, promotes the browning of beige fat cells in white adipose tissue ([Figure 1](#F1){ref-type="fig"}), resulting in enhanced thermogenesis and increased energy expenditure ([@B45]). In the CNS ([Figure 2](#F2){ref-type="fig"}), FCDN5/irisin regulates central mechanisms that mediate adaptive responses by (a) improving neuronal mitochondrial decoupling and (b) increasing the expression of neurotrophins and neuroprotective proteins such as neuronal PAS domain protein 4 (NPAS4), cFOS, activity-regulated cytoskeleton-associated protein (ARC), and zinc finger protein 268 (ZIF268) ([Figure 1](#F1){ref-type="fig"}; [@B102]; [@B101]). In brown adipose tissue, mitochondrial uncoupling is effected by a specific protein, referred to as uncoupling protein-1 (UCP1), in the inner mitochondrial membrane ([@B81]). The cloning of UCP2 and UCP3, two homologs of UCP1, has boosted research into the importance of respiration control in metabolic processes, metabolic diseases and energy balance ([@B81]). PPAR-γ/PGC-1α expression also improves mitochondrial decoupling, which reduces mitochondrial membrane potential and reactive oxygen species (ROS) production, oxidative damage, mitochondrial calcium overload and potential apoptotic events through the induction of uncoupling protein 2 (UCP2) ([@B7]). Therefore, FND5/irisin is essential for processes involving neurotrophins and synaptic plasticity, mitochondrial biogenesis, and resistance to neuronal stress ([@B102]; [@B62]; [@B78]).

![The mechanism of action of irisin in metabolism-associated health issues or metabolic diseases. The expression of Arc, cFos, and Zif268 is induced by neuronal activity. BDNF, brain-derived neurotrophic factor; ERRα, estrogen-related receptor alpha; FNDC5, fibronectin domain-containing protein 5; PGC-1α, peroxisome proliferator-activated receptor gamma coactivator-1-alpha; TrkB, tyrosine receptor kinase B; WAT, white adipose tissue.](fnins-13-00292-g001){#F1}

![The exercise-increased circulating protein irisin links structural and functional modifications in muscle and brain. BDNF, brain-derived neurotrophic factor; FNDC5, fibronectin type III domain-containing protein 5; UCP2, uncoupling protein 2.](fnins-13-00292-g002){#F2}

The purpose of this manuscript is to review the roles played by FND5/irisin and UCP2, which are important for energy metabolism, in the neuroprotective and antioxidant effects of physical activity in the CNS.

The Exercise-Induced Release of Irisin and Its Neuroprotective Effects
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Because irisin is an exercise-induced hormone (or myokine), it is unclear whether the physical exercise-related CNS benefits are attributable to irisin. Irisin is a 112 amino acid peptide that is cleaved (by an unknown protease) from the glycosylated type I membrane protein FNDC5 and released into the bloodstream in a PGC-1α-dependent manner through a muscle contraction-mediated transcription mechanism ([@B18]). PGC-1α is a transcriptional coactivator and does not bind to DNA directly; it needs to interact with another transcription factor to induce neuronal FNDC5 gene expression ([@B104]). Several clues indicate that the PGC-1α binding partner is orphan nuclear estrogen-related receptor alpha (ERRα) ([@B50]; [@B104]). Moreover, irisin enhances PGC-1α expression in the hippocampus and prefrontal cortex of mice in a positive feedback loop ([@B88]). The irisin released from muscles is a myokine that acts preferentially on the subcutaneous 'beige' fat and causes it to 'brown' by increasing the expression of UCP1 and other thermogenic genes ([@B18]). Irisin is involved in human biological adaptations such as increased muscle strength, decreased obesity and insulin resistance, and also has physical and psychological benefits ([@B18]; [@B40]). Currently, it is hypothesized that irisin circulates in the blood in vesicles containing other molecules, such as proteins, miRNA and nucleic acids, until reaching the target tissues, which include adipose tissue and the brain ([@B83]). The exercise-induced release of peptides and nucleic acids from skeletal muscle (collectively termed 'exerkines') has been implicated in mediating systemic biological adaptations ([@B83]).

The contraction of large muscle groups increases the muscle-specific expression of PGC1-α and FNDC5 and consequent release of irisin ([@B18]). In humans, blood irisin levels reach approximately 3.6 ng/ml in sedentary individuals and 4.3 ng/ml in active individuals after 12 weeks of regular aerobic exercise ([@B49]). Irisin contributes to exercise-induced physiological adaptations in the cardiovascular, immune, digestive, and adipose systems ([@B18]; [@B108]; [@B65]). In obese adult humans, exercise combined with caloric restriction improves health ([@B69]) and increases concentrations of circulating irisin ([@B47]). Although skeletal muscle is the major source of exercise-induced irisin that is released into the plasma ([@B82]), it remains unclear whether neuronal irisin is derived from muscles or is produced in neurons. In neurons, PGC-1α interacts with estrogen-related receptor alpha (ERRα) to regulate the expression of FNDC5 ([Figure 1](#F1){ref-type="fig"}; [@B102]). Moreover, the increased expression of FNDC5 promotes neuronal development and differentiation ([@B35]; [@B40]). FNDC5 can be found in the cerebrospinal fluid, cortical neurons, paraventricular neurons in the hippocampus, Purkinje cells in the cerebellum, hypothalamus, multipolar neurons in the anterior nerve of the spinal cord, and in astrocytes and microglia in the cerebral tissue ([@B28]; [@B68]; [@B74]; [@B6]). In the rat H19-7HN cell line, irisin (50--100 nmol/l) increased the proliferation of hippocampal cells, thus reinforcing its role in neurogenesis ([@B68]).

[@B102] demonstrated that the expression of PGC-1α and FNDC5 in the hippocampal neurons was enhanced after the mice spent 2 weeks running in exercise wheels. Higher FNDC5 expression also increased the expression of the genes BDNF, Arc, cFos, and Zif268, which is induced by neuronal activity. FNDC5 expression is counterbalanced by BDNF expression in a negative feedback mechanism ([Figure 1](#F1){ref-type="fig"}; [@B102]). It is possible that this feedback loop is a CNS detraining mechanism that requires regular exercise to maintain its neurological benefits. This evidence suggests that the induction of FNDC5 is part of the transcriptional response to exercise, including neuroplasticity and neuroprotection, in the CNS. Exercise-induced PGC-1α and irisin reduced ischemia-induced neuronal injury ([@B107]) via activation of the Akt and ERK1/2 signaling pathways in mice ([@B56]). Exercise-induced irisin also reduced the brain infarct volume, neurological deficits, brain edema and the body weight decline of mice subjected to middle cerebral artery occlusion (MCAO) ([@B56]). Since BDNF is a critical regulator of neural plasticity, irisin may act as a key regulator of neuronal survival following cerebral ischemia. Physical activity (running wheel, 12 weeks) increases levels of circulating irisin and BDNF even in 20-month-old female rats ([@B12]), increases the expression of BDNF and decreases neuroinflammation in the hippocampus of aged rats and mice, and has motor and cognitive benefits ([@B1]; [@B24]).

Exercise is an antidepressant ([@B15]; [@B23]), and irisin has been linked to the antidepressant effects of exercise. Reduced irisin levels are associated with mood impairment and reduced BDNF levels in humans ([@B71]; [@B90]), and increased circulating concentrations of irisin have been shown to have antidepressant effects in mice ([@B88]). A possible mechanism for the antidepressant effect is the activation of the PGC-1α/BDNF pathway by irisin after exercise ([@B102]). As previously mentioned, BDNF is a critical neurotrophin involved in the differentiation, survival, maintenance, and function of neurons; it is also involved in learning and memory processes ([@B102]). [@B94] demonstrated that the neurotrophic role of BDNF is dependent on PGC-1α.

In humans, the increased plasma levels of FNDC-5, irisin and BDNF seem to depend on exercising large muscle groups, as can be achieved with regular Nordic walking training ([@B41]), aquarobics (16 weeks) ([@B51]), and CrossFit training (12 weeks) ([@B70]). The electrical stimulation of small muscle groups increases BDNF but not irisin in the hippocampus of rats ([@B60]). In healthy elderly women, Nordic walking training improved body composition, anaerobic capacity and cardiovascular fitness ([@B41]), and CrossFit training improved psychological (Quality-of-Life Assessment and The Beck Depression Inventory-2) and cognitive functions (D2 test of attention and Trail Making Test A&B).

Neuronal UCP2 --An Antioxidant Mechanism of Exercise
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The expression of neuronal uncoupling proteins (UCP) is induced by metabolic and oxidative challenges such as physical exercise and caloric restriction ([@B58]). UCP facilitates proton flux through the internal mitochondrial membrane, thereby dissociating the oxidative phosphorylation of ATP synthesis ([@B98]). The enhanced proton flux process reduces the mitochondrial membrane potential, increases mitochondrial respiration, decreases the ATP/ADP ratio, and dissipates chemical energy in the form of heat ([@B21]). Acute mitochondrial decoupling reduces mitochondrial ATP production; however, chronic mitochondrial decoupling promotes an increase in the number of mitochondria and an increased level of ATP production ([@B22]).

Initially, UCP1, which functions in heat production, was identified in brown adipose tissue ([@B38]). UCP2 is found in organs and tissues such as the liver, kidney, pancreas, endothelium, immune cells, and the CNS ([@B73]; [@B21]). UCP2, UCP4, and UCP5 are expressed in the CNS, are referred to as neuronal U, and are involved in the adaptation to cellular stress ([@B21]). The distribution of neuronal UCPs demonstrates the relevance of mitochondrial decoupling in the CNS to the control of neuronal, neuroendocrine, and autonomic responses ([@B80]). UCP2 is expressed in the hypothalamus, especially in the arcuate nucleus, limbic system, cerebellum, choroid plexus, and encephalic trunk ([@B80]; [@B8]). UCP4 is detected in most brain tissues, but it is expressed at lower levels in the spinal cord and *Substantia nigra* ([@B61]). UCP5 is expressed in the cerebral cortex, hippocampus, thalamus, hypothalamus, amygdala, basal ganglia, and spinal cord ([@B53]).

Neuronal UCPs influence the regulation of mitochondrial biogenesis, calcium flux, ROS production, and local temperature ([@B91]). Neuronal UCPs play an important role in the reduction of ROS production and consequent reduction in oxidative stress without compromising the production of ATP ([@B8]). Exposure of cultured neurons to decoupling agents, such as carbonyl cyanide-4-(trifluoromethoxy) phenylhydrazone (FCCP) or 2,4-dinitrophenol (2,4-DNP or simply DNP), reduces the mitochondrial membrane potential and inhibits mitochondrial calcium absorption, and thus prevents cell death ([@B89]). Neuronal UCPs also influence the temperature of neuronal microenvironments and thus contribute to the dynamics of neuronal activity through greater synaptic plasticity and neuronal transmission ([@B8]). Some studies have suggested that mitochondrial decoupling is linked to neuroprotection against physiological processes and pathological mechanisms including aging, Alzheimer's and Parkinson's diseases, neuronal hypoxia and ischemia, and epilepsy ([@B11]; [@B26]).

Among the neuronal UCPs, UCP2 is involved in central autonomic, endocrine, and metabolic regulation and is thus associated with cognition, mood, and behavior ([@B25]; [@B96]). UCP2 in the ventromedial nucleus restores glucose tolerance and regulates insulin sensitivity mediated by glucose-excited neurons, which is important for the physiological control of systemic glucose metabolism ([@B93]). In the arcuate nucleus, UCP2 is associated with mitochondrial fission, increased mitochondrial density and diminished mitochondrial size ([@B93]). UCP2 shows increased expression after neuronal injury ([@B11]). UCP2 induces mitochondrial decoupling in nigral neurons of the substantia nigra pars compacta (SNpc) and can prevent the loss of dopaminergic cells after 1-methyl-4-phenyl-1,2,5,6-tetrahydropyridine (MPTP)-induced toxicity, which is an essential effect to delay Parkinson's disease pathophysiology ([@B29]; [@B46]). The relation of UCP2 to exercise occurs through the PGC-1α/PPARα pathway, which can regulate neuronal UCP2 ([@B103]) and BDNF ([@B42]). Physical activity (running wheel, 4 weeks) increased UCP2 expression and mitochondrial oxygen consumption in coupled and uncoupled mitochondria in the hippocampus of mice ([@B26]). Moreover, physical activity (running wheel, 1 week) and exercise (treadmill, 12 weeks) increased UCP2 levels in the hippocampus, cerebellum and brain cortex mitochondria of adult rats ([@B42]; [@B64]). The exercise-induced (running wheel, 1 week) increase in UCP2 correlated with increased BDNF in the hippocampus of rats ([@B42]). These changes in BDNF content and mitochondrial metabolism ([@B95]; [@B5], [@B3]) coincided with an increase in the number of mitochondria and dendritic spine synapses in the granule cells of the dentate gyrus and the stratum radiatum of the CA1 region and were dependent on UCP2 expression because such changes were not observed in UCP2 knockout mice ([@B26]). The absence of proper mitochondrial decoupling reduced the number of synapses in hippocampal neurons due to the increase in free radical production in response to exercise, thus demonstrating the characteristic protective effect of UCP2 in this knockout mouse model ([@B26]). For example, doxorubicin is an effective antineoplastic agent that is limited by mitochondrial toxicity in non-target tissues, including the brain ([@B63]; [@B33]). Doxorubicin (2 mg/kg, i.p.) impaired spatial learning/memory and decreased UCP2 protein content in cerebellum and brain cortex mitochondria of adult rats, both of which were prevented by physical activity (treadmill, 12 weeks) ([@B63]). The UCP2-related nuclear respiration factor 1 (NRF1) and mitochondrial transcription factor A (TFAM) genes, which are involved in mitochondrial biogenesis, are associated with synaptic plasticity and decreased neuronal vulnerability to cellular stress ([@B87]). In an animal model of Parkinson's disease, 8 weeks of treadmill exercise stimulated mitochondrial biogenesis and increased NRF2 and TFAM expression in the striatum of mice, which protected against neuronal death caused by the neurotoxin 6-OHDA ([@B2]). The mitochondrial mechanism related to UCP2 function is essential for the appropriate bioenergetic adaptation of neurons to increased neuronal activity and synaptic plasticity in response to physical activity.

Conclusion
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Exercise improves the PGC-1α/BDNF pathway (muscle/brain) through the signaling of circulating irisin, which strengthens synapses and exhibits neuroprotective and antidepressant effects. These neuroprotective effects of exercise are enhanced by the antioxidant effects of UCP2, which is expressed at increased levels in neurons in response to exercise. Therefore, the evidence suggests a role for irisin/UCP2 in the mechanism underlying the benefits of physical exercise on the CNS. Consequently, irisin/UCP2 might be a potential therapeutic target to improve brain function and prevent or treat neurological and neurodegenerative diseases.

Author Contributions
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All authors listed have made a substantial, direct and intellectual contribution to the work, and approved it for publication.

Conflict of Interest Statement
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The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

**Funding.** The work was supported by CAPES (Coordenação de Aperfeiçoamento de Pessoal de Nível Superior), CNPq (Conselho Nacional de Desenvolvimento Científico e Tecnológico), and FAPESC (Fundação de Amparo à Pesquisa e Inovação do Estado de Santa Catarina). AA was a CNPq fellow.

[^1]: Edited by: Sebastien Talbot, Université de Montréal, Canada

[^2]: Reviewed by: Sung Ung Kang, Johns Hopkins University, United States; Matthew Lawrence Goodwin, Johns Hopkins Medicine, United States

[^3]: This article was submitted to Neuroenergetics, Nutrition and Brain Health, a section of the journal Frontiers in Neuroscience
