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Exercise hormone irisin is a critical regulator of cognitive function

An Author Correction to this article was published on 07 October 2021

This article has been updated

Abstract

Identifying secreted mediators that drive the cognitive benefits of exercise holds great promise for the treatment of cognitive decline in ageing 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 benefits of exercise on cognitive function. Genetic deletion of Fndc5/irisin (global Fndc5 knock-out (KO) mice; F5KO) impairs cognitive function in exercise, ageing and AD. Diminished pattern separation in F5KO mice 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 the cognitive benefits of exercise and is a potential therapeutic agent for treating cognitive disorders including AD.

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Fig. 1: Genetic deletion of irisin impairs cognitive function in exercise and ageing.
Fig. 2: Pattern separation is impaired in F5KO mice and can be rescued by delivering irisin directly into the DG.
Fig. 3: Adult-born neurons, but not mature granule cells, in the hippocampus display aberrant activation in global F5KO mice.
Fig. 4: Adult-born neurons in the hippocampus develop abnormally in global F5KO mice.
Fig. 5: The transcriptome of adult-born neurons in the hippocampus is altered in global F5KO mice.
Fig. 6: Peripheral irisin improves cognitive function in transgenic mouse models of AD.
Fig. 7: Peripheral irisin reduces glia activation in transgenic mouse models of AD.
Fig. 8: Peripherally delivered irisin crosses the blood–brain barrier.

Data availability

RNA-seq datasets are available at the Gene Expression Omnibus repository under accession number GSE174212, which contains the GSE174210, GSE174211 and GSE179078 datasets. Markers for astrocytes and microglia are available from http://dropviz.org. Data from the MSSM study are available from https://www.synapse.org/. The single-cell data are available from http://linnarssonlab.org/dentate/. Source data are provided with this paper.

Code availability

The code for the RNA-seq data analysis from the MSSM study is available in the Supplementary Information.

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Acknowledgements

This work was supported by National Institutes of Health (NIH) grant nos. NS087096, AG062904 and AG064580 (to C.D.W.), 1R01AR065538, 1R01CA193520, R01DK062472 and S10RR027931 (to R.J.S.), K01DK089145 and R01DK062472 (to A.B.S.); the Cure Alzheimer’s Fund (to C.D.W., S.H.C. and R.E.T.); an Alzheimer Association Research Grant (to C.D.W.), a SPARC Award from the McCance Center for Brain Health (to C.D.W.), the NeuroBehavior Laboratory Pilot Project Research Award from the Harvard NeuroDiscovery Center (to C.D.W.), the Hassenfeld Clinical Scholar Award (to C.D.W.), the Claflin Distinguished Scholar Award (to C.D.W.), the Harvard Brain Science Initiative Young Scientist Travel Award (to M.R.I.), the MSFHR (to B.R.C. and L.E.B.B.), the FRAXA (to B.R.C. and L.E.B.B.), the FXRFC (to B.R.C. and L.E.B.B.), the NSERC (to B.R.C. and L.E.B.B.), the CIHR (to B.R.C. and L.E.B.B.), the JPB Foundation (to B.M.S.) and the MGH Molecular Imaging Core (to R.J.S.). We thank H. Van Praag for critical comments on the study design, data analysis and the manuscript, and for providing us with the RV-CAG-GFP and RV-SYN-GTRgp. We acknowledge K. Gerber for technical assistance. We thank all members of the laboratory of C.D.W. for helpful discussions. We thank L. Djenoune for great help with Adobe Illustrator. We thank Z. Herbert from the Molecular Biology Core Facilities at the Dana-Farber Cancer Institute for support. We acknowledge J. Long for help with designing the AAV8-irisin. We acknowledge the MGH Viral Vector Core (supported by NIH/NINDS P30NS04776) and the Penn Vector core for technical and instrument support. Schematic icons in Figs. 4 and 5 were created with BioRender.com.

Author information

Authors and Affiliations

Authors

Contributions

M.R.I., S.V., M.F.Y., R.L., E.B.H., S.F.B., S.M. and C.D.W. performed and analysed the in vivo experiments. S.V., E.B.H., M.R.I. and S.F.B. performed and analysed the in vitro experiments. M.P.J. provided conceptual and experiment advice on the irisin plasma analysis. R.R.K. performed bioinformatical analysis. L.E.B.B. and B.R.C. conceived, performed and analysed the electrophysiological experiments. A.B.S. and R.J.S. performed and analysed the dSTORM microscopy. H.T. and E.K. contributed to the data interpretation. H.K. and B.M.S. designed and generated AAV8-irisin with the Penn Vector core. B.J.C., S.H.C. and R.E.T. provided scientific input. B.M.S. provided conceptual advice. C.D.W. directed the research. M.R.I., S.V. and C.D.W. co-wrote the paper with assistance from all other authors.

Corresponding author

Correspondence to Christiane D. Wrann.

Ethics declarations

Competing interests

The authors declare the following competing interests: B.M.S. and C.D.W. hold a patent related to irisin (WO2015051007A1). B.M.S. and C.D.W. are academic co-founders and consultants for Aevum Therapeutics. C.D.W. has a financial interest in Aevum Therapeutics, a company developing drugs that harness the protective molecular mechanisms of exercise to treat neurodegenerative and neuromuscular disorders. C.D.W.’s interests were reviewed and are managed by MGH and Mass General Brigham in accordance with their conflict-of-interest policies. The other authors declare no competing interests.

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Peer review information Primary Handling Editor: Christoph Schmitt. Nature Metabolism thanks the anonymous reviewers for their contribution to the peer review of this work.

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Extended data

Extended Data Fig. 1 Irisin deletion impairs cognitive function in exercise and aging.

a, Schematic of flox targeting-construct for the Fndc5 locus. b, Bodyweights (WT-sed n = 9; WT-run n = 12; F5KO-sed n = 12; F5KO-run, n = 14). c, qPCR of Fndc5 mRNA expression (n.d.: no detection) (n = 3 per group). d and e, Plasma irisin with commercial ELISA (n = 4 per group) (d) or EIA (n = 2 per group) (e). f, Rotarod, g, Grip strength, h, Gait scan analysis: average propulsion (left) and swing time (right). FR = front right limb, FL = front left, RR = rear right, RL = rear left (WT n = 6, F5KO n = 10), i, Open field test (OPF) (WT-sed n = 5; WT-run n = 6; F5KO-sed n = 6; F5KO-run n = 6), and j, Running activity and k and l, Morris-water-maze (MWM): latency to reach target platform (k) and 24 h probe trial in acquisition (l). NE (red bar) was the target quadrant (WT-sed n = 9; WT-run, n = 12; F5KO-sed n = 12; F5KO-run, n = 14). m, Swim speed, 9-months-old mice (WT, n = 10, F5KO, n = 10). n and o, Novel object recognition (NOR) task in young (n) (WT n = 12, F5KO, n = 14) and aged mice (o) (WT n = 5, F5KO, n = 7). p and q, Bodyweights (p) and Open field test (OPF) (q) for aged mice (WT n = 8, F5KO, n = 7). r, Spontaneous alternation behavior (SAB) in aged mice (WT, n = 7, F5KO, n = 7). s and t, Electrophysiology in DG using acute slices, paired pulse ratio (s) and EPSP input-output curve (t) (WT n = 14, F5KO n = 15 slices, 7 animals per group,). RM-Two-way ANOVA (k, t), Two-way ANOVA (b, h, i), One-way ANOVA. Significance was assigned only if time spent in the target quadrant was significantly different from all other quadrants (l), Two-tailed t-test (d-g, j, m-s). ***p < 0.001, ****p < 0.0001 n.s.= not significant. Data represented as mean ± SEM of biologically independent samples. See source data for exact p-values.

Source data

Extended Data Fig. 2 Pattern separation is impaired in F5KO mice and can be rescued by delivering irisin directly into the dentate gyrus.

a, Elevated plus maze. b, Tail suspension test. c and d, Baseline freezing in CFC-DL (c) and in CFC (d) of WT and F5KO mice. e and f, WT and F5KO stereotaxically injected with AAV8-GFP or AAV8-irisin-FLAG into the DG. Representative immunofluorescence images, GFP (green), irisin-FLAG (red), NeuN (magenta) in the hippocampus. Scale bar 200 µm (e) and baseline freezing in the CFC-DL (f) (WT n = 10, F5KO n = 12 (a, b, d); n = 9 per group (c); WT-GFP n = 10, WT-irisin n = 10, F5KO-GFP n = 9, F5KO-irisin n = 10 (f)). RM-Two-way ANOVA (b), One-Way ANOVA (f), Two-tailed t-test (a, c, d). n.s.= not significant. Data are represented as mean ± SEM of biologically independent samples.

Source data

Extended Data Fig. 3 Adult-born neurons in the hippocampus are altered in global F5KO mice.

a and b, Quantification (a) and representative immunohistochemistry images (b) of BrdU+ adult-born hippocampal neurons in WT and F5KO mice (n = 6 per group). Scale bar 100 μm. c and d, Quantification (c) and representative immunofluorescence images (d) of EdU+ adult-born hippocampal neurons in WT and F5KO mice with or without running exercise (WT-sed n = 8, WT-run n = 10, F5KO n = 8, F5KO-run n = 13). Scale bar 100 μm. e, Soma size of adult-born hippocampal neurons (WT-sed n = 60, WT-run n = 60, F5KO-sed n = 65, F5KO-run n = 64 neurons). f-h, Dendritic spine analysis of newborn neurons in the ventral hippocampus. Dendritic spines density (f), cumulative distribution of spine head width (g), and median spine head width (h) (WT-sed n = 7, WT-run n = 6, F5KO-sed n = 7, F5KO-run n = 6 (f); WT-sed n = 1239, WT-run n = 1056, F5KO-sed n = 1089, F5KO-run n = 1047 spines (g); WT-sed n = 7, WT-run n = 6, F5KO-sed n = 6, F5KO-run n = 6 (h)). i-l, Dendritic spine analysis in mature granule cells in the dentate gyrus of Thy1-GFP/WT and Thy1-GFP/F5KO. Representative confocal images of dendritic spines stained with anti-GFP (green). Scale bar 5 µm (i), dendritic spines density (j), cumulative distribution of spine head width (k), and median spine head width (l) (n = 5 per group (j, l); WT n = 921, F5KO n = 948 spines (k)). Two-way ANOVA (c, e, f, h), Kruskal-Wallis ANOVA (g), Kolmogorov-Smirnov test (k), Two-tailed t-test (a, j, l). *p < 0.05, ****p < 0.0001, n.s.= not significant. Data are represented as mean ± SEM of biologically independent samples, except for violin plots with center line = median, dotted line = upper and lower quartile (e). See source data for exact p-values.

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Extended Data Fig. 4 The transcriptome of adult-born neurons in the hippocampus is altered in global F5KO mice.

a and b, Representative FACS density plots of single nuclei isolated from the hippocampus of a non-injected WT control mouse (a) and a RV-Syn-GTRgp-GFP injected mouse (b). Nuclei were stained with Vybrant DyeCycle stain to label intact nuclei. c, Volcano plot of DESeq2 analysis of bulk RNA-sequencing of microdissected dentate gyrus from F5KO and WT mice (n = 5 per group).

Extended Data Fig. 5 Genetic deletion of irisin impairs cognitive function in transgenic mouse models of AD.

a and b, MSD ELISA for Aβ-40 and Aβ-42 peptides in soluble fraction of hippocampus (a) and cortex (b) (APP/PS1-WT n = 2, APP/PS1-F5KO n = 3). c, Body weights at 6 months old. d and e, Open field test (OPF). f, Spontaneous Alternation Behavior (SAB). g, Baseline freezing in CFC. n = 10 per group (c, f, g); n = 7 per group (d, e). RM-Two-way ANOVA (d, e), Two-way ANOVA (a, b), Two-tailed t-test (c, f, g). **p < 0.01, n.s.= not significant. Data are represented as mean ± SEM of biologically independent samples. See source data for exact p-values.

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Extended Data Fig. 6 Peripheral irisin improves cognitive function in APP/PS1 transgenic mouse model of AD.

APP/PS1 mice were injected with AAV8-GFP or AAV8-irisin-FLAG via the tail vein. a, Liver (GFP n = 14, irisin n = 11) b, Hippocampus “irisin” mRNA expression (GFP n = 5, irisin n = 5), c, Bodyweights at the beginning and end of the experiment, d and e, OPF test, f, SAB (GFP n = 15, irisin n = 11). g, Barnes Maze, escape latency to hole (GFP n = 9, irisin n = 5), h-j, Morris-water-maze (MWM) latency to reach the target platform (h) and 24 h probe trial in in acquisition (i). SW quadrant (blue bar) was the target quadrant. Latency to reach the target platform in reversal (j) (GFP n = 6, irisin n = 6). k and l, Baseline freezing (k) and freezing in CFC (l), m, CFC-DL (n = 6 per group). RM-Two-way ANOVA (c, d, e, g left, h, j, l, m), One-way ANOVA followed by Fisher’s LSD. Significance was assigned only if time spent in the target quadrant was significantly different from all other quadrants (i), Two-tailed t-test (b, f, g right, k), Two-tailed t-test with Welch’s correction (a). *p < 0.05, **p < 0.01, n.s.= not significant. Data are represented as mean ± SEM of biologically independent samples. See source data for exact p-values.

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Extended Data Fig. 7 Peripheral irisin improves cognitive function in 5xFAD transgenic mouse model of AD.

5xFAD mice were injected with AAV8-GFP or AAV8-irisin-FLAG via the tail vein. a, Liver b, Hippocampus “irisin” mRNA expression (n = 3 per group). c, Bodyweights at the beginning and end of the experiment, d and e, OPF test, f, SAB. g-j, Morris-water-maze (MWM) latency to reach the target platform in acquisition (g) and 24 h probe trial in MWM in acquisition (h). NE quadrant (green bar) was the target quadrant. Latency to reach the target platform in reversal (i) and 24 h probe trial in MWM reversal (j). SW quadrant (green bar) was the target quadrant. k and l, CFC, baseline freezing (k) and freezing in CFC (l) (GFP n = 11, irisin n = 10 (c-f, k, l); GFP n = 8, irisin n = 7 (g-j)). RM-Two-way ANOVA (c, d, e, g, i, l), One-way ANOVA followed by Fisher’s LSD. Significance was assigned only if time spent in the target quadrant was significantly different from all other quadrants (h, j), Two-tailed t-test (a, b, f, k). *p < 0.05, **p < 0.01, ****p < 0.0001, n.s.= not significant, data are represented as mean ± SEM of biologically independent samples. See source data for exact p-values.

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Extended Data Fig. 8 Peripheral irisin reduces glia activation in transgenic mouse models of AD.

APP/PS1 mice were injected with AAV8-GFP or AAV8-irisin-FLAG via the tail vein. a, Expression of synaptic plasticity genes in hippocampus derived from normalized read counts of RNA-seq analysis (GFP n = 5, irisin n = 5), b, MSD ELISA for Abeta40 peptide in cortex soluble fraction, c, MSD ELISA Abeta42 peptide in cortex soluble fraction (GFP n = 9, irisin n = 5). d and e, Representative immunofluorescence confocal images of hippocampus, GFAP (green), Iba-1 (red), 3D6 (Alexa 647). Scale bar 200 μm (d) and quantification of plaque burden in hippocampus (e) (GFP n = 7, irisin n = 5). f, Quantification of plaque burden cortex (GFP n = 5, irisin n = 3). g, Quantification of total BrdU+ cells (GFP n = 7, irisin n = 5). Two-way ANOVA (a), Two-tailed t-test (b, c, e-g). n.s.= not significant, data are represented as mean ± SEM of biologically independent samples.

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Extended Data Fig. 9 Irisin binds αV/β5 integrin receptor on astrocytes in adult hippocampal neural stem cells cultures.

a, Two-color dSTORM images of integrin αV/β3 (left) and αV/β5 (right) (green) and irisin-FLAG (red) molecules. Scale bar 5 μm (irisin-FLAG-αV/β3 n = 7, irisin-FLAG-αV/β5 n = 10), b and c, Itgav gene expression (b) and Itgb5 gene expression (c) in the murine dentate gyrus from Linnarsson lab database (https://linnarssonlab.org/dentate/)59. d, QPCR analysis of mRNA expression of Map2, Dcx, Gfap, and Aif1 in the dentate gyrus (n = 6) and neurons differentiated from adult hippocampal stem cells (n = 8 from two independent experiments). Ct: cycle threshold value. Data are represented as mean ± SEM of biologically independent samples.

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Extended Data Fig. 10 Peripherally delivered irisin has central effects.

a-e, WT mice injected with AAV8-GFP or AAV8-irisin-FLAG via the tail vein. Western blot of plasma from AAV8-GFP (1-2) and AAV8-irisin-FLAG (3-4) with or without deglycosylation (a), qPCR analysis of liver (b), quadriceps (c), inguinal white adipose tissue (iWAT) (d), interscapular brown adipose tissue (iBAT) (e). Two-way ANOVA (b-d). Data are represented as mean ± SEM of biologically independent samples (n = 6 per group) (b-e).

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Islam, M.R., Valaris, S., Young, M.F. et al. Exercise hormone irisin is a critical regulator of cognitive function. Nat Metab 3, 1058–1070 (2021). https://doi.org/10.1038/s42255-021-00438-z

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