Exercise hormone irisin is a critical regulator of cognitive function

Abstract

Identifying secreted mediators driving the cognitive benefits of exercise holds great promise for the treatment of cognitive decline in aging or Alzheimer’s disease (AD). Here, we show that irisin, the cleaved and circulating form of the exercise-induced membrane protein FNDC5, is sufficient to confer the exercise benefits on cognitive function. Genetic deletion of FNDC5/irisin (global F5KO mice) impairs cognitive function in exercise, aging, and AD. Diminished pattern separation in F5KOs can be rescued by delivering irisin directly into the dentate gyrus, suggesting that irisin is the active moiety. In F5KO mice, adult-born neurons in the dentate gyrus are morphologically, transcriptionally, and functionally abnormal. Importantly, elevation of circulating irisin levels by peripheral delivery of irisin via adeno-associated viral overexpression in the liver, results in enrichment of central irisin and is sufficient to improve both the cognitive deficit and neuropathology in AD mouse models. Irisin is a crucial regulator of cognitive benefits of exercise and potential therapeutic for treating cognitive disorders including AD.

The Role of Decorin Proteoglycan in Mitophagy

“…There is also evidence that Irisin, a soluble peptide of 112 amino acids derived from the transmembrane protein called fibronectin type III domain containing protein 5 (FNDC5) [184], can positively affect mitophagy [185]. Indeed, Irisin mitigates oxidative stress and chondrocyte dysfunction through retaining mitochondrial biogenesis, dynamics, and autophagy [185] Moreover, Irisin is an exercise-induced myokine abundant in skeletal muscle and facilitates the positive impact of moderate exercise on tissue physiology and cognitive function [186,187]. Notably, PGC1-α activates FNDC5 to increase the secretion of Irisin [184] and, as mentioned above, decorin evokes mitophagy in breast carcinoma cells via PGC-1α and mitostatin [76].…”

Ghrelin Acylation—A Post-Translational Tuning Mechanism Regulating Adult Hippocampal Neurogenesis

“…Notably, environmental factors such as exercise and enriched home cages for rodents enhance NSPC proliferation [ 34 ] and the differentiation and survival [ 35 ] of new adult-born neurones, respectively. These phenomena have led to the identification of several factors generated outside of the CNS that regulate adult hippocampal neurogenesis (AHN), including irisin [ 36 ], klotho [ 37 ], cathepsin B [ 38 ], clusterin [ 39 ], eotaxin [ 40 ], growth differentiation factor11 (GDF11) [ 41 ], β 2 microglobulin (B2M) [ 42 ], and glycosylphosphatidylinositol-specific phospholipase D1 (Gpld1) [ 43 ]. Similarly, calorie restriction increases AHN primarily by supporting differentiation and survival [ 44 ] via ghrelin signalling [ 12 , 45 ].…”

Molecular targets of exercise mimetics and their natural activators

“…In addition, exercise increases the hippocampal expression of FNDC5, the precursor of irisin, in mice, in a PGC-1α-dependent manner ( 28 ). Irisin stimulates neurogenesis, synaptic plasticity, and cognitive function by upregulating the expression of brain-derived neurotrophic factor (BDNF), demonstrating that irisin may act as a link between exercise and brain function ( 29 ).…”