Evidence map›Paper›PMID 34417591›Full record

ArticleNature metabolism2021

Exercise hormone irisin is a critical regulator of cognitive function.

Mohammad R Islam, Sophia Valaris, Michael F Young, Erin B Haley, Renhao Luo, Sabrina F Bond, Sofia Mazuera, Robert R Kitchen, Barbara J Caldarone, Luis E B Bettio and 12 more

Erratum issuedOpen access · greenAbstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Nature metabolism, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. An erratum has been issued. Cited by 226 papers, 6 of them syntheses that pooled it.

0numbers the graph read from it
0cells of the map it votes in
226citing papers in PubMed, 6 pooled it
30.6field-weighted citation impact, top 1% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

226 citing papers in PubMed, 6 syntheses or guidelines pooled it, 360 citations in OpenAlex.

  1. Pooled it
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  7. Trial
  8. Review
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  10. A peripheral perspective on brain health: vascular and skeletal muscle contributions.American journal of physiology. Heart and circulatory physiology · 2026
    Review
  11. Article
  12. Exercise and Fat: A Primer.Sports medicine - open · 2026
    Review
  13. Article
  14. Review
  15. Article
  16. Review
  17. Article
  18. Article
  19. Article
  20. Article

166 more citing papers are in PubMed but not listed here.

4 · The record

Corrections and comments

5 · Who and what money

Authors and funding

22 authors at 6 institutions in 2 countries.

Mohammad R Islam *Cardiovascular Research Center, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
Sophia Valaris *Cardiovascular Research Center, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
Michael F YoungCardiovascular Research Center, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
Erin B HaleyCardiovascular Research Center, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
Renhao LuoCardiovascular Research Center, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
Sabrina F BondCardiovascular Research Center, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
Sofia MazueraCardiovascular Research Center, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
Robert R KitchenCardiovascular Research Center, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.ORCID http://orcid.org/0000-0003-1443-8559
Barbara J CaldaroneHarvard NeuroDiscovery Center, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
Luis E B BettioDivision of Medical Sciences, University of Victoria, Victoria, British Colombia, Canada.
Brian R ChristieDivision of Medical Sciences, University of Victoria, Victoria, British Colombia, Canada.ORCID http://orcid.org/0000-0002-6830-0160
Angela B SchmiderNephrology Division, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
Roy J SobermanNephrology Division, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
Antoine BesnardCenter for Regenerative Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.ORCID http://orcid.org/0000-0002-0929-8873
Mark P JedrychowskiDepartment of Cancer Biology, Dana-Farber Cancer Institute and Department of Cell Biology, Harvard Medical School, Boston, MA, USA.
Hyeonwoo KimDepartment of Cancer Biology, Dana-Farber Cancer Institute and Department of Cell Biology, Harvard Medical School, Boston, MA, USA.
Hua TuLakePharma, San Carlos, CA, USA.
Eunhee KimMassGeneral Institute for Neurodegenerative Disease, Genetics and Aging Research Unit, Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA, USA.
Se Hoon ChoiMassGeneral Institute for Neurodegenerative Disease, Genetics and Aging Research Unit, Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA, USA.
Rudolph E TanziMassGeneral Institute for Neurodegenerative Disease, Genetics and Aging Research Unit, Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA, USA.ORCID http://orcid.org/0000-0002-7032-1454
Bruce M SpiegelmanDepartment of Cancer Biology, Dana-Farber Cancer Institute and Department of Cell Biology, Harvard Medical School, Boston, MA, USA.ORCID http://orcid.org/0000-0002-7658-4802
Christiane D WrannCardiovascular Research Center, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA. cwrann@mgh.harvard.edu.ORCID http://orcid.org/0000-0001-6066-8799
Harvard University · USNortheastern University · USUniversity of Victoria · CABrigham and Women's Hospital · USLakePharma (United States) · USMassachusetts General Hospital · US

Funding

Interdepartmental Neuroscience CenterP30NS045776 · NINDS · MASSACHUSETTS GENERAL HOSPITAL · PI BREAKEFIELD, XANDRA OWENS, TANNOUS, BAKHOS A · 2003 to 2018
$11.1M
Role of B7-1 in Podocytes in Pathogenesis of ProteinuriaR01DK062472 · NIDDK · UNIVERSITY OF MIAMI SCHOOL OF MEDICINE · PI SOBERMAN, ROY · 2004 to 2017
$5.3M
Ly6 family members in neutrophil biologyR01AR065538 · NIAMS · BRIGHAM AND WOMEN'S HOSPITAL · PI NIGROVIC, PETER A · 2014 to 2024
$4.0M
FNDC5/irisin as a Molecular Mediator of Exercise Benefits in Cognitive FunctionR01NS117694 · NINDS · MASSACHUSETTS GENERAL HOSPITAL · PI Christiane D. Wrann · 2022 to 2026
$2.5M
The Role of lncRNA MEG3 in Clinically Non-functioning Pituitary AdenomasR01CA193520 · NCI · MASSACHUSETTS GENERAL HOSPITAL · PI SOBERMAN, ROY · 2016 to 2020
$1.9M
The Macromolecular Organization of Leukotriene Synthesis and Renal InflammationK01DK089145 · NIDDK · MASSACHUSETTS GENERAL HOSPITAL · PI SCHMIDER, ANGELA BAIR · 2011 to 2015
$798k
Molecular mechanisms of exercise benefits in synapse plasticity and cognitionR00NS087096 · NINDS · MASSACHUSETTS GENERAL HOSPITAL · PI WRANN, CHRISTIANE D. · 2017 to 2019
$745k
Dissecting the molecular mediators of the neuroprotective effects of exercise in Alzheimer's DiseaseR56AG064580 · NIA · MASSACHUSETTS GENERAL HOSPITAL · PI WRANN, CHRISTIANE D. · 2019 to 2019
$590k
Exploring irisin as a novel target for Alzheimer's DiseaseR21AG062904 · NIA · MASSACHUSETTS GENERAL HOSPITAL · PI CHOI, SE HOON, WRANN, CHRISTIANE D. · 2019 to 2020
$462k
A System for FLIM MicroscopyS10RR027931 · NCRR · MASSACHUSETTS GENERAL HOSPITAL · PI SOBERMAN, ROY · 2010 to 2010
$321k
Molecular mechanisms of exercise benefits in synapse plasticity and cognitionK99NS087096 · NINDS · DANA-FARBER CANCER INST · PI WRANN, CHRISTIANE D. · 2014 to 2015
$223k
NCI NIH HHS R01 CA193520NCRR NIH HHS S10 RR027931NIAMS NIH HHS R01 AR065538NIA NIH HHS R21 AG062904NIA NIH HHS R56 AG064580NIDDK NIH HHS K01 DK089145NIDDK NIH HHS R01 DK062472NINDS NIH HHS K99 NS087096NINDS NIH HHS P30 NS045776NINDS NIH HHS R00 NS087096NINDS NIH HHS R01 NS117694
6 · The paper itself

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.

Indexed as

CognitionPhysical Conditioning, AnimalAnimalsBehavior, AnimalCognition DisordersDisease Models, AnimalFibronectinsGene DeletionGene ExpressionHormonesMiceMice, KnockoutPhenotypeFibronectinsFNDC5 protein, mouseHormones

Identifiers

PMID34417591
PMCPMC10317538
OpenAlexW3194164206

What OpenQuestion holds

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Registered trials

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.