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Can Irisin Be a Linker Between Physical Activity and Brain Function?

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Can Irisin Be a Linker Between Physical Activity and Brain Function? BioMol Concepts 2016; 7(4): 253–258 Review Jing Zhang and Weizhen Zhang* Can irisin be a linker between physical activity and brain function? DOI 10.1515/bmc-2016-0012 Parkinson’s disease (PD) (1). Recently, a large-scale 5-year Received March 16, 2016; accepted May 17, 2016 prospective study in human subjects has demonstrated that regular physical activity could represent an impor- Abstract: Irisin was initially discovered as a novel hor- tant and potent protective factor for cognitive decline mone-like myokine released from skeletal muscle during and dementia in the elders (2). Animal studies also dem- exercise to improve obesity and glucose dysfunction by onstrate that exercise and/or behavioral enrichment sig- stimulating the browning of white adipose tissue. Emerg- nificantly improves brain function measured by neuronal ing evidence have indicated that irisin also affects brain survival and resistance to brain insult (3, 4), brain vascu- function. FNDC5 mRNA and FNDC5/irisin immunoreac- larization (5, 6), neurogenesis (7), learning (7, 8), as well tivity are present in various regions of the brain. Central as maintenance of cognitive function during aging (9, 10). irisin is involved in the regulation of neural differentiation Increased levels of neurotrophins in the central and proliferation, neurobehavior, energy expenditure nervous system have been proposed to mediate the ben- and cardiac function. Elevation of peripheral irisin level eficial effects of regular physical activity. Among these stimulates hippocampal genes related to neuroprotection, neurotrophins, brain-derived neurotrophic factor (BDNF), learning and memory. In this brief review, we summarize insulin-like growth factor (IGF-1), vascular endothelial the current understanding on neuronal functions of irisin. growth factor (VEGF), fibroblast growth factor (FGF-2), In addition, we discuss the pros and cons for this mol- epidermal growth factor (EGF) and never growth factor ecule as a potential messenger mediating the crosstalk (NGF) are well characterized to increase survival, prolif- between skeletal muscle and central nervous system dur- eration and maturation of specific neurons in the brain ing exercise. (11). Emerging evidences also suggest a peripheral mecha- Keywords: brain function; exercise; FNDC5; irisin; nism. Peripheral tissues such as adipose tissue and skel- myokine. etal muscle may respond to exercise by producing leptin (12) and irisin (13) that bolster brain function. Irisin, whose name derives from the Greek goddess Iris (messenger of the gods), is a novel hormone-like myokine Introduction released from skeletal muscle during exercise. This 112 amino acid peptide is cleaved from fibronectin type III The beneficial effects of physical activity for brain health domain containing protein 5 (FNDC5) (14). FNDC5/irisin and function have been recognized for centuries. Regular has been found to be expressed robustly not only in skel- physical activity reduces a number of mental disorders etal muscle (14) but also in various regions of brain tissue such as depression and anxiety, as well as attenuates the (15–17). Since its discovery in 2012, this molecule has onset and progression of Alzheimer’s disease (AD) and gained huge interest as a potential mediator of the health promoting effects of physical exercise. Exercise increases *Corresponding author: Weizhen Zhang, Department of Surgery, Fndc5 gene expression in skeletal muscle, leading to sub- University of Michigan Medical Center, 1150 W. Medical Center Drive, sequent increment in circulating irisin (14, 18). Similarly, Ann Arbor, MI 48109-0346, USA; and Department of Physiology and endurance exercise increases expression of FNDC5 in the Pathophysiology, Peking University HealthScience Center, Beijing hippocampus (13). Overexpression of Fndc5 in the liver 100091, China, e-mail: [email protected] results in significant elevation of circulating irisin. The Jing Zhang: Department of Surgery, University of Michigan Medical Center, 1150 W. Medical Center Drive, Ann Arbor, MI 48109-0346, change in blood irisin is associated with a marked incre- USA; and School of Physical Education and Sports, Beijing Normal ment in the expression of Bdnf and other neuroprotective University, Beijing 100875, China genes in the hippocampus (13). All these findings suggest 254 J. Zhang and W. Zhang: Irisin and the brain that irisin may serve as a critical molecule linking regular Bdnf and other neuroprotective genes in the hippocampus. exercise with health and diseases of the brain. In this brief This effect is presumably mediated by irisin because its review, we summarize current understanding on the neu- circulating level is significantly elevated. Further investi- ronal function of irisin. We will also discuss the pros and gation should aim to characterize the direct regulation of cons for this molecule as a potential messenger mediating neural differentiation and proliferation by irisin. the crosstalk between skeletal muscle and central nervous system during exercise. Neurobehavioral effects of irisin The finding (13) that peripheral overexpression of Fndc5 Irisin in brain function induces increment in BDNF expression in hippocampus hints that irisin may function to improve learning and Emerging evidence has indicated that irisin may function memory by the BDNF pathway. Bdnf, a notable neuro- as a neurotrophic factor to promote survival, maintenance trophin, promotes many aspects of brain development and function of neuronal cells. including neuronal cell survival, differentiation, migra- tion, dendritic arborization, synaptogenesis and plasticity Effects of irisin on neural differentiation (24). BNDF is also essential for hippocampal function in learning and memory (25). Further, levels of cFos, Arc, and The function of FNDC5 on neural differentiation was first Zif268 in hippocampus and forebrain, which are impor- discovered by a research team from Iran. Also named tant indicators for the activity state of neurons, increase PeP transcript because it was independently discovered significantly in mice overexpressing Fndc5 (13). Together in a search for peroxisomal proteins, FNDC5 was ini- with the findings that endurance exercise elevates levels tially demonstrated to be significantly increased after of circulating irisin, these results suggest the poten- retinoic acid induction during the neural differentiation tial neurotrophic function of irisin. Irisin may thus be a of mouse embryonic stem cells in neural precursor cells critical molecule linking the beneficial effects of regular and neurospheres (19). This finding indicates that FNDC5 physical activity with the neurobehavioral improvement. might be involved in the early regulation of neurogen- This concept is further supported by our recent studies. esis. Knockdown of Fndc5 in mouse embryonic stem cells Administration of irisin by third intracerebroventricular significantly reduces expression of both neural progeni- (ICV) injection causes an abrupt and transient increase tors and mature neuronal markers, which results in the in locomotor activity, including total travel distance, reduction of both neuronal and astrocyte maturation (20). ambulatory counts and time (26). Interestingly, peripheral On the other hand, overexpression of Fndc5 significantly administration of irisin demonstrates no effect on locomo- increases neural differentiation precursor markers and tor activity (26). mature neuron markers. All these data suggest that FNDC5 However, it is worthy to note that direct application of may facilitate neural differentiation (21). Further studies irisin to cultured hippocampal neurons demonstrates neg- (22) indicate that FNDC5 stimulates neural differentiation ligible effect on the expression of Bdnf gene (13). Whether via the extracellular-signal-regulated kinase 1/2(ERK1/2) irisin regulates the hippocampal function via an indirect signaling pathway. mechanism remains to be investigated. Unlike its precursor FNDC5, irisin is less convincingly demonstrated to directly regulate neurogenesis. At physi- ologic concentrations from 5 to 10 nm, irisin demonstrates Cardiac function of central irisin no effect on neuronal cell proliferation in cultured H19-7 cells, a mouse hippocampal cell line. Only pharmacologi- Endurance exercise increases cardiac function. Our studies cal doses of irisin (50–100 nm) increase cell proliferation provide evidence supporting that irisin may contribute to by 70%–80%. This alteration is mediated by the signal the beneficial effect of exercise on cardiac function. Central transducer and activator of transcription 3 (STAT3) signal- administration of irisin significantly increases both sys- ing pathway (23). Further, neither physiological doses nor tolic and diastolic blood pressure. Further, heart rate and pharmacological concentrations of irisin affect neurite cardiac output dose-dependently increase immediately outgrowth and synaptogenesis in cultured H19-7 cells. In following injection of 0.625, 1.25 and 2.5 μg irisin into the contrast, a recent study by Wrann et al. (13) shows that 3rd ventricle (27). These cardiotropic effects of central irisin hepatic overexpression of Fndc5 induces expression of may occur through activation of paraventricular nucleus J. Zhang and W. Zhang: Irisin and the brain 255 (PVN) neurons in the hypothalamus. Vasopressin but not Is irisin synthesized and released from norepinephrine may be responsible for pressor effects of FNDC5 in the central nervous system? central irisin. Conversely, other studies
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