FNDC5/Irisin – Their Role in the Nervous System and as a Mediator for Beneficial Effects of Exercise on the Brain

Abstract

Exercise can improve cognitive function and the outcome of neurodegenerative diseases, like Alzheimer’s disease. This effect has been linked to the increased expression of brain-derived neurotrophic factor (BDNF). However, the underlying molecular mechanisms driving the elevation of this neurotrophin remain unknown. Recently, we have reported a PGC-1α-FNDC5/irisin pathway, which is activated by exercise in the hippocampus in mice and induces a neuroprotective gene program, including Bdnf. This review will focus on FNDC5 and its secreted form “irisin”, a newly discovered myokine, and their role in the nervous system and its therapeutic potential. In addition, we will briefly discuss the role of other exercise-induced myokines on positive brain effects.

Irisin increases the expression of anorexigenic and neurotrophic genes in mouse brain

“…In addition, Lourenco et al have recently demonstrated that peripheral overexpression of FNDC5/irisin rescues memory impairment, whereas blockade of peripheral FNDC5/irisin attenuates the neuroprotective actions of physical exercise on synaptic plasticity and memory in an Alzheimer mice model. These data indicate that either irisin itself can cross the blood–brain barrier to induce brain effects or that irisin may induce another peripheral unknown factor with such a property …”

“…For all these reasons, irisin is considered a critical myokine related to body metabolism. Moreover, increasing evidence proposes irisin also as a mediator of the beneficial effects of exercise on the brain function (memory) and in neurodegenerative diseases …”

“…Moreover, increasing evidence proposes irisin also as a mediator of the beneficial effects of exercise on the brain function (memory) and in neurodegenerative diseases. [13][14][15] Although it was demonstrated that irisin expression is detectable around the paraventricular nucleus region in human hypothalamic sections where it colocalizes with NPY, 16 the potential role of irisin in the regulation of body weight and food intake is still unclear. Indeed, irisin administration has been shown to promote weight loss in diabetic mice or rats, [17][18][19][20][21][22] but other studies showed no differences in body weight between diabetic mice receiving irisin or not.…”

Adaptive Capacity: An Evolutionary Neuroscience Model Linking Exercise, Cognition, and Brain Health

“…In addition, Kempermann (2008) suggests that novelty and exploration may be key elements of these combined physical and cognitive challenges. Recent work provides a clue as to how movement triggers production of neurotrophins critical for neuroplasticity [64]. In rodent models, exercising muscles produce myokines, including FNDC5 and cathepsin B, which regulate metabolic processes and may improve muscle function while also inducing increased levels of BDNF [64–66].…”

Running-Induced Systemic Cathepsin B Secretion Is Associated with Memory Function

“…Indeed, overexpression of peroxisome proliferator-activated receptor-gamma co-activator (PGC-1α) in muscle increased production of Fibronectin type III domain containing 5 (FNDC5), which is cleaved and secreted as irisin, increasing hippocampal Bdnf expression. Exercise elevates irisin in human plasma (Wrann, 2015). Furthermore, PGC-1α1 overexpression in muscle has an antidepressant-like effect by reducing entry of neurotoxic kynurenine into the brain (Agudelo et al, 2014).…”