Progress and Challenges in the Biology of FNDC5 and Irisin

Steffen Maak, Frode Norheim, Christian A Drevon, Harold P Erickson, Steffen Maak, Frode Norheim, Christian A Drevon, Harold P Erickson

Abstract

In 2002, a transmembrane protein-now known as FNDC5-was discovered and shown to be expressed in skeletal muscle, heart, and brain. It was virtually ignored for 10 years, until a study in 2012 proposed that, in response to exercise, the ectodomain of skeletal muscle FNDC5 was cleaved, traveled to white adipose tissue, and induced browning. The wasted energy of this browning raised the possibility that this myokine, named irisin, might mediate some beneficial effects of exercise. Since then, more than 1000 papers have been published exploring the roles of irisin. A major interest has been on adipose tissue and metabolism, following up the major proposal from 2012. Many studies correlating plasma irisin levels with physiological conditions have been questioned for using flawed assays for irisin concentration. However, experiments altering irisin levels by injecting recombinant irisin or by gene knockout are more promising. Recent discoveries have suggested potential roles of irisin in bone remodeling and in the brain, with effects potentially related to Alzheimer's disease. We discuss some discrepancies between research groups and the mechanisms that are yet to be determined. Some important questions raised in the initial discovery of irisin, such as the role of the mutant start codon of human FNDC5 and the mechanism of ectodomain cleavage, remain to be answered. Apart from these specific questions, a promising new tool has been developed-mice with a global or tissue-specific knockout of FNDC5. In this review, we critically examine the current knowledge and delineate potential solutions to resolve existing ambiguities.

Keywords: FNDC5; bone; brain; irisin; metabolism; myokine.

© The Author(s) 2021. Published by Oxford University Press on behalf of the Endocrine Society.

Figures

Graphical Abstract
Graphical Abstract
Figure 1.
Figure 1.
Structure of FNDC5 and irisin. (A) Schematic structure of the mouse FNDC5 protein with functional units (upper part). Diagram of the FNDC5 protein. The FNIII domain is in color, with beta strands vertical and connecting loops horizontal. The mature irisin peptide runs from the signal peptide cleavage site to the proposed irisin cut site (lower part). (B) Ribbon diagram of the irisin dimer (pdb 4LSD chains A,B, (5). The C’ strands pair to form a continuous eight-strand beta sheet in the dimer. Asn36 and Asn81, the putative sites of N-linked glycosylation, are shown in black sticks. (C) A model of transmembrane FNDC5, where the linker between the FNIII domain and the transmembrane helix is shown as unstructured coil. The cleavage step should involve a secretase but this has not been explored. Alternatively, the dimeric FNDC5 could function as a transmembrane receptor, with unknown ligand. Figures B and C were constructed in PyMOl (The PyMOL Molecular Graphics System, Version 2.0 Schrödinger, LLC).
Figure 2.
Figure 2.
Plasma concentrations of irisin measured with ELISA methodologies in human (blue) and mice (green). The numbers given on the arrowheads represent the lowest and highest irisin levels (units on the x-axis) reported for the specific assay in both species. All values are means or medians of control groups. Concentrations measured by quantitative MS for humans and mice are marked by arrows above the graph and on the x-axis.
Figure 3.
Figure 3.
Exercise increases PGC1α in skeletal muscle of mice and humans. The subsequent increase in FNDC5 is established in mice but not in humans. FNDC5 may reside as dimeric transmembrane receptor, for example, in skeletal muscle, bone, and brain. The putative cleavage mechanism releasing the extracellular part as irisin is still unclear. Irisin acts on WAT and induces browning, is involved in bone remodeling and improves cognition and memory. Many of these effects have been shown by application of r-irisin to cells or by injections into mice. Browning of WAT was induced by application of high doses of r-irisin or by forced ectopic expression of FNDC5 in mice but was not shown in humans so far. Further open questions are: Does irisin enhance bone formation or resorption or both in a dose dependent manner? Does irisin cross the BBB to increase FNDC5 and BDNF levels as was demonstrated for exercise kynurenic acid, lactate, and cathepsin B? In a recent report (155) a liver-to-brain axis was established with a central role of exercise-induced, liver-derived GPLD1. The figure was partly created with biorender.org. Abbreviations: BDNF, brain-derived neurotrophic factor; BBB, blood-brain barrier; FNDC5, Fibronectin type III domain-containing protein 5; GPI, glycosylphosphatidyl inositol; GPLD1, GPI–specific phospholipase D1; OPG, osteoprotegerin; PGC1α, peroxisome proliferator-activated receptor gamma coactivator 1 alpha; r-Irisin, recombinant irisin; SOST, sclerostin; UCP1, uncoupling protein 1; WAT, white adipose tissue.

References

    1. Ferrer-Martínez A, Ruiz-Lozano P, Chien KR. Mouse PeP: a novel peroxisomal protein linked to myoblast differentiation and development. Dev Dyn. 2002;224(2):154-167.
    1. Teufel A, Malik N, Mukhopadhyay M, Westphal H. Frcp1 and Frcp2, two novel fibronectin type III repeat containing genes. Gene. 2002;297(1-2):79-83.
    1. Boström P, Wu J, Jedrychowski MP, et al. A PGC1-α-dependent myokine that drives brown-fat-like development of white fat and thermogenesis. Nature. 2012;481(7382):463-468.
    1. Cannon B, Nedergaard J. Brown adipose tissue: function and physiological significance. Physiol Rev. 2004;84(1):277-359.
    1. Schumacher MA, Chinnam N, Ohashi T, Shah RS, Erickson HP. The structure of irisin reveals a novel intersubunit β-sheet fibronectin type III (FNIII) dimer: implications for receptor activation. J Biol Chem. 2013;288(47):33738-33744.
    1. Komolka K, Albrecht E, Schering L, Brenmoehl J, Hoeflich A, Maak S. Locus characterization and gene expression of bovine FNDC5: is the myokine irisin relevant in cattle? Plos One. 2014;9(1):e88060.
    1. Raschke S, Elsen M, Gassenhuber H, et al. Evidence against a beneficial effect of irisin in humans. Plos One. 2013;8(9):e73680.
    1. Jedrychowski MP, Wrann CD, Paulo JA, et al. Detection and Quantitation of Circulating Human Irisin by Tandem Mass Spectrometry. Cell Metab. 2015;22(4):734-740.
    1. Ivanov IP, Firth AE, Michel AM, Atkins JF, Baranov PV. Identification of evolutionarily conserved non-AUG-initiated N-terminal extensions in human coding sequences. Nucleic Acids Res. 2011;39(10):4220-4234.
    1. Pirastu M, Saglio G, Chang JC, Cao A, Kan YW. Initiation codon mutation as a cause of alpha thalassemia. J Biol Chem. 1984;259(20):12315-12317.
    1. Eiken HG, Knappskog PM, Apold J, Skjelkvåle L, Boman H. A de novo phenylketonuria mutation: ATG (Met) to ATA (Ile) in the start codon of the phenylalanine hydroxylase gene. Hum Mutat. 1992;1(5):388-391.
    1. Caridi G, Dagnino M, Lugani F, et al. A novel mutation in the albumin gene (c.1A > C) resulting in analbuminemia. Eur J Clin Invest. 2013;43(1):72-78.
    1. Kozak M. Context effects and inefficient initiation at non-AUG codons in eucaryotic cell-free translation systems. Mol Cell Biol. 1989;9(11):5073-5080.
    1. Albrecht E, Schering L, Buck F, et al. Irisin: still chasing shadows. Mol Metab. 2020;34:124-135.
    1. Ruan Q, Zhang L, Ruan J, et al. Detection and quantitation of irisin in human cerebrospinal fluid by tandem mass spectrometry. Peptides. 2018;103:60-64.
    1. Albrecht E, Norheim F, Thiede B, et al. Irisin - a myth rather than an exercise-inducible myokine. Sci Rep. 2015;5:8889.
    1. Roca-Rivada A, Castelao C, Senin LL, et al. FNDC5/irisin is not only a myokine but also an adipokine. Plos One. 2013;8(4):e60563.
    1. Löffler D, Müller U, Scheuermann K, et al. Serum irisin levels are regulated by acute strenuous exercise. J Clin Endocrinol Metab. 2015;100(4):1289-1299.
    1. Matsuo Y, Gleitsmann K, Mangner N, et al. Fibronectin type III domain containing 5 expression in skeletal muscle in chronic heart failure-relevance of inflammatory cytokines. J Cachexia Sarcopenia Muscle. 2015;6(1):62-72.
    1. Deng J, Zhang N, Wang Y, et al. FNDC5/irisin improves the therapeutic efficacy of bone marrow-derived mesenchymal stem cells for myocardial infarction. Stem Cell Res Ther. 2020;11(1):228.
    1. Lee P, Linderman JD, Smith S, et al. Irisin and FGF21 are cold-induced endocrine activators of brown fat function in humans. Cell Metab. 2014;19(2):302-309.
    1. Wrann CD, White JP, Salogiannnis J, et al. Exercise induces hippocampal BDNF through a PGC-1α/FNDC5 pathway. Cell Metab. 2013;18(5):649-659.
    1. Hayashida K, Bartlett AH, Chen Y, Park PW. Molecular and cellular mechanisms of ectodomain shedding. Anat Rec (Hoboken). 2010;293(6):925-937.
    1. Nie Y, Dai B, Guo X, Liu D. Cleavage of FNDC5 and insights into its maturation process. Mol Cell Endocrinol. 2020;510:110840.
    1. Lourenco MV, Frozza RL, de Freitas GB, et al. Exercise-linked FNDC5/irisin rescues synaptic plasticity and memory defects in Alzheimer’s models. Nat Med. 2019;25(1):165-175.
    1. Kim H, Wrann CD, Jedrychowski M, et al. Irisin Mediates Effects on Bone and Fat via αV Integrin Receptors. Cell. 2018;175(7):1756-1768.e17.
    1. Polyzos SA, Mathew H, Mantzoros CS. Irisin: a true, circulating hormone. Metabolism. 2015;64(12):1611-1618.
    1. Erickson HP. Irisin and FNDC5 in retrospect: an exercise hormone or a transmembrane receptor? Adipocyte. 2013;2(4):289-293.
    1. Gul-Kahraman K, Yilmaz-Bozoglan M, Sahna E. Physiological and pharmacological effects of melatonin on remote ischemic perconditioning after myocardial ischemia-reperfusion injury in rats: role of Cybb, Fas, NfκB, Irisin signaling pathway. J Pineal Res. 2019;67(2):e12589.
    1. Brenmoehl J, Albrecht E, Komolka K, et al. Irisin is elevated in skeletal muscle and serum of mice immediately after acute exercise. Int J Biol Sci. 2014;10(3):338-349.
    1. Chen K, Xu Z, Liu Y, et al. Irisin protects mitochondria function during pulmonary ischemia/reperfusion injury. Sci Transl Med. 2017;9(418):eaao6298.
    1. Huh JY, Panagiotou G, Mougios V, et al. FNDC5 and irisin in humans: I. Predictors of circulating concentrations in serum and plasma and II. mRNA expression and circulating concentrations in response to weight loss and exercise. Metabolism. 2012;61(12):1725-1738.
    1. Stengel A, Hofmann T, Goebel-Stengel M, Elbelt U, Kobelt P, Klapp BF. Circulating levels of irisin in patients with anorexia nervosa and different stages of obesity–correlation with body mass index. Peptides. 2013;39:125-130.
    1. Choi YK, Kim MK, Bae KH, et al. Serum irisin levels in new-onset type 2 diabetes. Diabetes Res Clin Pract. 2013;100(1):96-101.
    1. Lawson EA, Ackerman KE, Slattery M, Marengi DA, Clarke H, Misra M. Oxytocin secretion is related to measures of energy homeostasis in young amenorrheic athletes. J Clin Endocrinol Metab. 2014;99(5):E881-E885.
    1. Perakakis N, Triantafyllou GA, Fernández-Real JM, et al. Physiology and role of irisin in glucose homeostasis. Nat Rev Endocrinol. 2017;13(6):324-337.
    1. Aslan R, Alp HH, Eryılmaz R, et al. Can the Irisin be a Biomarker for Prostate Cancer? A Case Control Study. Asian Pac J Cancer Prev. 2020;21(2):505-509.
    1. Tang L, Tong Y, Zhang F, et al. The association of circulating irisin with metabolic risk factors in Chinese adults: a cross-sectional community-based study. BMC Endocr Disord. 2019;19(1):147.
    1. Bi J, Zhang J, Ren Y, et al. Irisin alleviates liver ischemia-reperfusion injury by inhibiting excessive mitochondrial fission, promoting mitochondrial biogenesis and decreasing oxidative stress. Redox Biol. 2019;20:296-306.
    1. Natalicchio A, Marrano N, Biondi G, et al. The Myokine Irisin Is Released in Response to Saturated Fatty Acids and Promotes Pancreatic β-Cell Survival and Insulin Secretion. Diabetes. 2017;66(11):2849-2856.
    1. Boeselt T, Nell C, Lütteken L, et al. Benefits of High-Intensity Exercise Training to Patients with Chronic Obstructive Pulmonary Disease: A Controlled Study. Respiration. 2017;93(5):301-310.
    1. Bang HS, Seo DY, Chung YM, et al. Ursolic Acid-induced elevation of serum irisin augments muscle strength during resistance training in men. Korean J Physiol Pharmacol. 2014;18(5):441-446.
    1. Li DJ, Huang F, Lu WJ, Jiang GJ, Deng YP, Shen FM. Metformin promotes irisin release from murine skeletal muscle independently of AMP-activated protein kinase activation. Acta Physiol (Oxf). 2015;213(3):711-721.
    1. Zhou X, Li R, Liu X, et al. ROCK1 reduces mitochondrial content and irisin production in muscle suppressing adipocyte browning and impairing insulin sensitivity. Sci Rep. 2016;6:29669.
    1. Fukushima Y, Kurose S, Shinno H, et al. Effects of Body Weight Reduction on Serum Irisin and Metabolic Parameters in Obese Subjects. Diabetes Metab J. 2016;40(5):386-395.
    1. Kuzmicki M, Telejko B, Lipinska D, et al. Serum irisin concentration in women with gestational diabetes. Gynecol Endocrinol. 2014;30(9):636-639.
    1. Küster OC, Laptinskaya D, Fissler P, et al. Novel Blood-Based Biomarkers of Cognition, Stress, and Physical or Cognitive Training in Older Adults at Risk of Dementia: Preliminary Evidence for a Role of BDNF, Irisin, and the Kynurenine Pathway. J Alzheimers Dis. 2017;59(3):1097-1111.
    1. Huh JH, Ahn SV, Choi JH, Koh SB, Chung CH. High Serum Irisin Level as an Independent Predictor of Diabetes Mellitus: A Longitudinal Population-Based Study. Medicine (Baltimore). 2016;95(23):e3742.
    1. Amengual J, García-Carrizo FJ, Arreguín A, et al. Retinoic Acid Increases Fatty Acid Oxidation and Irisin Expression in Skeletal Muscle Cells and Impacts Irisin In Vivo. Cell Physiol Biochem. 2018;46(1):187-202.
    1. Quiñones M, Folgueira C, Sánchez-Rebordelo E, Al-Massadi O. Circulating Irisin Levels Are Not Regulated by Nutritional Status, Obesity, or Leptin Levels in Rodents. Mediators Inflamm. 2015;2015:620919.
    1. Kałużna M, Hoppe K, Schwermer K, Ibrahim AY, Pawlaczyk K, Ziemnicka K. Adropin and irisin levels in relation to nutrition, body composition, and insulin resistance in patients with end-stage renal disease on chronic hemodialysis and peritoneal dialysis. Pol Arch Med Wewn. 2016;126(7-8):474-482.
    1. Palermo A, Sanesi L, Colaianni G, et al. A Novel Interplay Between Irisin and PTH: From Basic Studies to Clinical Evidence in Hyperparathyroidism. J Clin Endocrinol Metab. 2019;104(8):3088-3096.
    1. Zhang M, Chen P, Chen S, et al. The association of new inflammatory markers with type 2 diabetes mellitus and macrovascular complications: a preliminary study. Eur Rev Med Pharmacol Sci. 2014;18(11):1567-1572.
    1. Bubak MP, Heesch MWS, Shute RJ, et al. Irisin and Fibronectin Type III Domain-Containing 5 Responses to Exercise in Different Environmental Conditions. Int J Exerc Sci. 2017;10(5):666-680.
    1. Yang S, Xiao F, Pan L, et al. Association of serum irisin and body composition with chronic kidney disease in obese Chinese adults: a cross-sectional study. BMC Nephrol. 2015;16:16.
    1. Moreno-Navarrete JM, Ortega F, Serrano M, et al. Irisin is expressed and produced by human muscle and adipose tissue in association with obesity and insulin resistance. J Clin Endocrinol Metab. 2013;98(4):E769-E778.
    1. Wiecek M, Szymura J, Sproull J, Szygula Z. Whole-Body Cryotherapy Is an Effective Method of Reducing Abdominal Obesity in Menopausal Women with Metabolic Syndrome. J Clin Med. 2020;9(9):E2797.
    1. Hofmann T, Elbelt U, Ahnis A, et al. The exercise-induced myokine irisin does not show an association with depressiveness, anxiety and perceived stress in obese women. J Physiol Pharmacol. 2016;67(2):195-203.
    1. Xiong XQ, Chen D, Sun HJ, et al. FNDC5 overexpression and irisin ameliorate glucose/lipid metabolic derangements and enhance lipolysis in obesity. Biochim Biophys Acta. 2015;1852(9):1867-1875.
    1. Ge X, Sathiakumar D, Lua BJ, Kukreti H, Lee M, McFarlane C. Myostatin signals through miR-34a to regulate Fndc5 expression and browning of white adipocytes. Int J Obes (Lond). 2017;41(1):137-148.
    1. Ghanbari-Niaki A, Saeidi A, Ahmadian M, et al. The combination of exercise training and Zataria multiflora supplementation increase serum irisin levels in postmenopausal women. Integr Med Res. 2018;7(1):44-52.
    1. Wang W, Guo Y, Zhang X, Zheng J. Abnormal irisin level in serum and endometrium is associated with metabolic dysfunction in polycystic ovary syndrome patients. Clin Endocrinol (Oxf). 2018;89(4):474-480.
    1. Ates I, Arikan MF, Erdogan K, et al. Factors associated with increased irisin levels in the type 1 diabetes mellitus. Endocr Regul. 2017;51(1):1-7.
    1. Yeniocak S, Karcıoğlu Ö, Kalkan A, et al. The diagnostic value of irisin in patients with acute abdominal pain: a preliminary study. Ulus Travma Acil Cerrahi Derg. 2018;24(6):539-544.
    1. Shi G, Tang N, Qiu J, et al. Irisin stimulates cell proliferation and invasion by targeting the PI3K/AKT pathway in human hepatocellular carcinoma. Biochem Biophys Res Commun. 2017;493(1):585-591.
    1. Hou N, Du G, Han F, Zhang J, Jiao X, Sun X. Irisin Regulates Heme Oxygenase-1/Adiponectin Axis in Perivascular Adipose Tissue and Improves Endothelial Dysfunction in Diet-Induced Obese Mice. Cell Physiol Biochem. 2017;42(2):603-614.
    1. Mustafa AI, El-Shimi OS. Serum irisin: a prognostic marker for severe acne vulgaris. J Cosmet Dermatol. 2018;17(5):931-934.
    1. Calan M, Demirpence M. Increased circulating levels of irisin are associated with cardiovascular risk factors in subjects with acromegaly. Hormones (Athens). 2019;18(4):435-442.
    1. Pang M, Yang J, Rao J, et al. Time-Dependent Changes in Increased Levels of Plasma Irisin and Muscle PGC-1α and FNDC5 after Exercise in Mice. Tohoku J Exp Med. 2018;244(2):93-103.
    1. Norheim F, Langleite TM, Hjorth M, et al. The effects of acute and chronic exercise on PGC-1α, irisin and browning of subcutaneous adipose tissue in humans. Febs J. 2014;281(3):739-749.
    1. Kurdiova T, Balaz M, Vician M, et al. Are Skeletal Muscle & Adipose Tissue Fndc5 Gene Expression and Irisin Release Affected by Obesity, Diabetes and Exercise? In vivo & in vitro studies. J Physiol. 2014;592(5):1091–1107.
    1. Montes-Nieto R, Martínez-García MÁ, Luque-Ramírez M, Escobar-Morreale HF. Differences in analytical and biological results between older and newer lots of a widely used irisin immunoassay question the validity of previous studies. Clin Chem Lab Med. 2016;54(7):e199-e201.
    1. Peng H, Wang Q, Lou T, et al. Myokine mediated muscle-kidney crosstalk suppresses metabolic reprogramming and fibrosis in damaged kidneys. Nat Commun. 2017;8(1):1493.
    1. Barja-Fernández S, Folgueira C, Castelao C, et al. FNDC5 is produced in the stomach and associated to body composition. Sci Rep. 2016;6:23067.
    1. Estell EG, Le PT, Vegting Y, et al. Irisin directly stimulates osteoclastogenesis and bone resorption in vitro and in vivo. Elife. 2020;9:e58172.
    1. Ruan Q, Huang Y, Yang L, et al. The effects of both age and sex on irisin levels in paired plasma and cerebrospinal fluid in healthy humans. Peptides. 2019;113:41-51.
    1. Zhang C, Ding Z, Lv G, Li J, Zhou P, Zhang J. Lower irisin level in patients with type 2 diabetes mellitus: a case-control study and meta-analysis. J Diabetes. 2016;8(1):56-62.
    1. Cui L, Qiao T, Xu F, et al. Circulating irisin levels of prenatal and postnatal patients with gestational diabetes mellitus: a systematic review and meta-analysis. Cytokine. 2020;126:154924.
    1. Qiu S, Cai X, Yin H, et al. Association between circulating irisin and insulin resistance in non-diabetic adults: a meta-analysis. Metabolism. 2016;65(6):825-834.
    1. Jia J, Yu F, Wei WP, et al. Relationship between circulating irisin levels and overweight/obesity: a meta-analysis. World J Clin Cases. 2019;7(12):1444-1455.
    1. Wang C, Zhang XY, Sun Y, Hou XG, Chen L. Higher circulating irisin levels in patients with polycystic ovary syndrome: a meta-analysis. Gynecol Endocrinol. 2018;34(4):290-293.
    1. Guo W, Zhang B, Wang X. Lower irisin levels in coronary artery disease: a meta-analysis. Minerva Endocrinol. 2020;45(1):61-69.
    1. Maalouf GE, El Khoury D. Exercise-Induced Irisin, the Fat Browning Myokine, as a Potential Anticancer Agent. J Obes. 2019;2019:6561726.
    1. Eslampour E, Ebrahimzadeh F, Abbasnezhad A, Khosroshahi MZ, Choghakhori R, Asbaghi O. Association between Circulating Irisin and C-Reactive Protein Levels: A Systematic Review and Meta-Analysis. Endocrinol Metab (Seoul). 2019;34(2):140-149.
    1. Zhou K, Qiao X, Cai Y, Li A, Shan D. Lower circulating irisin in middle-aged and older adults with osteoporosis: a systematic review and meta-analysis. Menopause. 2019;26(11):1302-1310.
    1. Rabiee F, Lachinani L, Ghaedi S, Nasr-Esfahani MH, Megraw TL, Ghaedi K. New insights into the cellular activities of Fndc5/Irisin and its signaling pathways. Cell Biosci. 2020;10:51.
    1. Moon HS, Dincer F, Mantzoros CS. Pharmacological concentrations of irisin increase cell proliferation without influencing markers of neurite outgrowth and synaptogenesis in mouse H19-7 hippocampal cell lines. Metabolism. 2013;62(8):1131-1136.
    1. Oguri Y, Shinoda K, Kim H, et al. CD81 Controls Beige Fat Progenitor Cell Growth and Energy Balance via FAK Signaling. Cell. 2020;182(3):563-577.e20.
    1. Zhang Y, Li R, Meng Y, et al. Irisin stimulates browning of white adipocytes through mitogen-activated protein kinase p38 MAP kinase and ERK MAP kinase signaling. Diabetes. 2014;63(2):514-525.
    1. Liu J, Song N, Huang Y, Chen Y. Irisin inhibits pancreatic cancer cell growth via the AMPK-mTOR pathway. Sci Rep. 2018;8(1):15247.
    1. Shan T, Liang X, Bi P, Kuang S. Myostatin knockout drives browning of white adipose tissue through activating the AMPK-PGC1α-Fndc5 pathway in muscle. Faseb J. 2013;27(5):1981-1989.
    1. Elsen M, Raschke S, Eckel J. Browning of white fat: does irisin play a role in humans? J Endocrinol. 2014;222(1):R25-R38.
    1. Abdullahi A, Jeschke MG. White Adipose Tissue Browning: A Double-edged Sword. Trends Endocrinol Metab. 2016;27(8):542-552.
    1. Trevellin E, Scorzeto M, Olivieri M, et al. Exercise training induces mitochondrial biogenesis and glucose uptake in subcutaneous adipose tissue through eNOS-dependent mechanisms. Diabetes. 2014;63(8):2800-2811.
    1. Xiong Y, Wu Z, Zhang B, et al. Fndc5 loss-of-function attenuates exercise-induced browning of white adipose tissue in mice. Faseb J. 2019;33(5):5876-5886.
    1. Lehnig AC, Dewal RS, Baer LA, et al. Exercise Training Induces Depot-Specific Adaptations to White and Brown Adipose Tissue. Iscience. 2019;11:425-439.
    1. Vitali A, Murano I, Zingaretti MC, Frontini A, Ricquier D, Cinti S. The adipose organ of obesity-prone C57BL/6J mice is composed of mixed white and brown adipocytes. J Lipid Res. 2012;53(4):619-629.
    1. Camera DM, Anderson MJ, Hawley JA, Carey AL. Short-term endurance training does not alter the oxidative capacity of human subcutaneous adipose tissue. Eur J Appl Physiol. 2010;109(2):307-316.
    1. Stinkens R, Brouwers B, Jocken JW, et al. Exercise training-induced effects on the abdominal subcutaneous adipose tissue phenotype in humans with obesity. J Appl Physiol (1985). 2018;125(5):1585-1593.
    1. Tsiloulis T, Carey AL, Bayliss J, Canny B, Meex RCR, Watt MJ. No evidence of white adipocyte browning after endurance exercise training in obese men. Int J Obes (Lond). 2018;42(4):721-727.
    1. Vosselman MJ, Hoeks J, Brans B, et al. Low brown adipose tissue activity in endurance-trained compared with lean sedentary men. Int J Obes (Lond). 2015;39(12):1696-1702.
    1. Otero-Díaz B, Rodríguez-Flores M, Sánchez-Muñoz V, et al. Exercise Induces White Adipose Tissue Browning Across the Weight Spectrum in Humans. Front Physiol. 2018;9:1781.
    1. Bettini S, Favaretto F, Compagnin C, et al. Resting Energy Expenditure, Insulin Resistance and UCP1 Expression in Human Subcutaneous and Visceral Adipose Tissue of Patients With Obesity. Front Endocrinol (Lausanne). 2019;10:548.
    1. Lim J, Park HS, Kim J, et al. Depot-specific UCP1 expression in human white adipose tissue and its association with obesity-related markers. Int J Obes (Lond). 2020;44(3):697-706.
    1. Timmons JA, Baar K, Davidsen PK, Atherton PJ. Is irisin a human exercise gene? Nature. 2012;488(7413):E9-10; discussion E10.
    1. Dinas PC, Lahart IM, Timmons JA, et al. Effects of physical activity on the link between PGC-1a and FNDC5 in muscle, circulating Ιrisin and UCP1 of white adipocytes in humans: a systematic review. F1000Res. 2017;6:286.
    1. Pillon NJ, Gabriel BM, Dollet L, et al. Transcriptomic profiling of skeletal muscle adaptations to exercise and inactivity. Nat Commun. 2020;11(1):470.
    1. Dehghani M, Kargarfard M, Rabiee F, Nasr-Esfahani MH, Ghaedi K. A comparative study on the effects of acute and chronic downhill running vs uphill running exercise on the RNA levels of the skeletal muscles PGC1-α, FNDC5 and the adipose UCP1 in BALB/c mice. Gene. 2018;679:369-376.
    1. Tiano JP, Springer DA, Rane SG. SMAD3 negatively regulates serum irisin and skeletal muscle FNDC5 and peroxisome proliferator-activated receptor γ coactivator 1-α (PGC-1α) during exercise. J Biol Chem. 2015;290(12):7671-7684.
    1. Pang M, Yang J, Rao J, et al. Time-Dependent Changes in Increased Levels of Plasma Irisin and Muscle PGC-1α and FNDC5 after Exercise in Mice. Tohoku J Exp Med. 2018;244(2):93-103.
    1. Abedpoor N, Taghian F, Ghaedi K, et al. PPARγ/Pgc-1α-Fndc5 pathway up-regulation in gastrocnemius and heart muscle of exercised, branched chain amino acid diet fed mice. Nutr Metab (Lond). 2018;15:59.
    1. Quinn LS, Anderson BG, Conner JD, Wolden-Hanson T. Circulating irisin levels and muscle FNDC5 mRNA expression are independent of IL-15 levels in mice. Endocrine. 2015;50(2):368-377.
    1. Lally JS, Ford RJ, Johar J, Crane JD, Kemp BE, Steinberg GR. Skeletal muscle AMPK is essential for the maintenance of FNDC5 expression. Physiol Rep. 2015;3(5):e12343.
    1. Colaianni G, Cuscito C, Mongelli T, et al. The myokine irisin increases cortical bone mass. Proc Natl Acad Sci U S A. 2015;112(39):12157-12162.
    1. Zhang Y, Li R, Meng Y, et al. Irisin stimulates browning of white adipocytes through mitogen-activated protein kinase p38 MAP kinase and ERK MAP kinase signaling. Diabetes. 2014;63(2):514-525.
    1. Zhu G, Wang J, Song M, et al. Irisin Increased the Number and Improved the Function of Endothelial Progenitor Cells in Diabetes Mellitus Mice. J Cardiovasc Pharmacol. 2016;68(1):67-73.
    1. Qiao X, Yong Qiao X, Nie Y, et al. Irisin promotes osteoblast proliferation and differentiation via activating the MAP kinase signaling pathways. Sci Rep. 2016;6:18732.
    1. Xin X, Wu J, Zheng A, et al. Delivery vehicle of muscle-derived irisin based on silk/calcium silicate/sodium alginate composite scaffold for bone regeneration. Int J Nanomedicine. 2019;14:1451-1467.
    1. Storlino G, Colaianni G, Sanesi L, et al. Irisin Prevents Disuse-Induced Osteocyte Apoptosis. J Bone Miner Res. 2020;35(4):766-775.
    1. Narayanan SA, Metzger CE, Bloomfield SA, Zawieja DC. Inflammation-induced lymphatic architecture and bone turnover changes are ameliorated by irisin treatment in chronic inflammatory bowel disease. Faseb J. 2018;32(9):4848-4861.
    1. Metzger CE, Narayanan SA, Elizondo JP, et al. DSS-induced colitis produces inflammation-induced bone loss while irisin treatment mitigates the inflammatory state in both gut and bone. Sci Rep. 2019;9(1):15144.
    1. Colaianni G, Mongelli T, Cuscito C, et al. Irisin prevents and restores bone loss and muscle atrophy in hind-limb suspended mice. Sci Rep. 2017;7(1):2811.
    1. Colucci S, Colaianni G, Brunetti G, et al. Irisin prevents microgravity-induced impairment of osteoblast differentiation in vitro during the space flight CRS-14 mission. Faseb J. 2020;34(8):10096-10106.
    1. Luo Y, Ma Y, Qiao X, et al. Irisin ameliorates bone loss in ovariectomized mice. Climacteric. 2020;23(5):496-504.
    1. Zhu X, Li X, Wang X, et al. Irisin deficiency disturbs bone metabolism. J Cell Physiol. 2021;236(1):664-676.
    1. Wucherpfennig TG, Müller S, Wolfrum C, Bode JW. Chemical Synthesis of the 12 kDa Human Myokine Irisin by α-Ketoacid-Hydroxylamine (KAHA) Ligation. Helv Chim Acta. 2016;99(12):897–907.
    1. Bi J, Zhang J, Ren Y, et al. Irisin reverses intestinal epithelial barrier dysfunction during intestinal injury via binding to the integrin αVβ5 receptor. J Cell Mol Med. 2020;24(1):996-1009.
    1. Bi J, Zhang J, Ren Y, et al. Exercise hormone irisin mitigates endothelial barrier dysfunction and microvascular leakage related diseases. JCI Insight. 2020b;5(13):e136277.
    1. Duong LT, Lakkakorpi P, Nakamura I, Rodan GA. Integrins and signaling in osteoclast function. Matrix Biol. 2000;19(2):97-105.
    1. Yavropoulou MP, Yovos JG. Osteoclastogenesis–current knowledge and future perspectives. J Musculoskelet Neuronal Interact. 2008;8(3):204-216.
    1. Franco OH, de Laet C, Peeters A, Jonker J, Mackenbach J, Nusselder W. Effects of physical activity on life expectancy with cardiovascular disease. Arch Intern Med. 2005;165(20):2355-2360.
    1. Ozemek C, Laddu DR, Lavie CJ, et al. An Update on the Role of Cardiorespiratory Fitness, Structured Exercise and Lifestyle Physical Activity in Preventing Cardiovascular Disease and Health Risk. Prog Cardiovasc Dis. 2018;61(5-6):484-490.
    1. Görgens SW, Eckardt K, Jensen J, Drevon CA, Eckel J. Exercise and Regulation of Adipokine and Myokine Production. Prog Mol Biol Transl Sci. 2015;135:313-336.
    1. Pérez-Martínez P, Mikhailidis DP, Athyros VG, et al. Lifestyle recommendations for the prevention and management of metabolic syndrome: an international panel recommendation. Nutr Rev. 2017;75(5):307-326.
    1. Smith PJ, Blumenthal JA, Hoffman BM, et al. Aerobic exercise and neurocognitive performance: a meta-analytic review of randomized controlled trials. Psychosom Med. 2010;72(3):239-252.
    1. Livingston G, Sommerlad A, Orgeta V, et al. Dementia prevention, intervention, and care. Lancet. 2017;390(10113):2673-2734.
    1. Pascoe MC, Parker AG. Physical activity and exercise as a universal depression prevention in young people: a narrative review. Early Interv Psychiatry. 2019;13(4):733-739.
    1. Pedersen BK. Physical activity and muscle-brain crosstalk. Nat Rev Endocrinol. 2019;15(7):383-392.
    1. Vanderlinden J, Boen F, van Uffelen JGZ. Effects of physical activity programs on sleep outcomes in older adults: a systematic review. Int J Behav Nutr Phys Act. 2020;17(1):11.
    1. Cotman CW, Berchtold NC, Christie LA. Exercise builds brain health: key roles of growth factor cascades and inflammation. Trends Neurosci. 2007;30(9):464-472.
    1. Norheim F, Raastad T, Thiede B, Rustan AC, Drevon CA, Haugen F. Proteomic identification of secreted proteins from human skeletal muscle cells and expression in response to strength training. Am J Physiol Endocrinol Metab. 2011;301(5):E1013-E1021.
    1. Moon HY, Becke A, Berron D, et al. Running-Induced Systemic Cathepsin B Secretion Is Associated with Memory Function. Cell Metab. 2016;24(2):332-340.
    1. De la Rosa A, Solana E, Corpas R, et al. Long-term exercise training improves memory in middle-aged men and modulates peripheral levels of BDNF and Cathepsin B. Sci Rep. 2019;9:3337.
    1. Sleiman SF, Henry J, Al-Haddad R, et al. Exercise promotes the expression of brain derived neurotrophic factor (BDNF) through the action of the ketone body β-hydroxybutyrate. Elife. 2016;5:e15092.
    1. Norwitz NG, Hu MT, Clarke K. The Mechanisms by Which the Ketone Body D-β-Hydroxybutyrate May Improve the Multiple Cellular Pathologies of Parkinson’s Disease. Front Nutr. 2019;6:63.
    1. Canli T, Lesch KP. Long story short: the serotonin transporter in emotion regulation and social cognition. Nat Neurosci. 2007;10(9):1103-1109.
    1. Dantzer R. Role of the Kynurenine Metabolism Pathway in Inflammation-Induced Depression: Preclinical Approaches. Curr Top Behav Neurosci. 2017;31:117-138.
    1. Schwarcz R, Bruno JP, Muchowski PJ, Wu HQ. Kynurenines in the mammalian brain: when physiology meets pathology. Nat Rev Neurosci. 2012;13(7):465-477.
    1. Schlittler M, Goiny M, Agudelo LZ, et al. Endurance exercise increases skeletal muscle kynurenine aminotransferases and plasma kynurenic acid in humans. Am J Physiol Cell Physiol. 2016;310(10):C836-C840.
    1. Contrepois K, Wu S, Moneghetti KJ, et al. Molecular Choreography of Acute Exercise. Cell. 2020;181(5):1112-1130.e16.
    1. Ma D, Li S, Lucas EK, Cowell RM, Lin JD. Neuronal inactivation of peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α) protects mice from diet-induced obesity and leads to degenerative lesions. J Biol Chem. 2010;285(50):39087-39095.
    1. Lourenco MV, Ribeiro FC, Sudo FK, et al. Cerebrospinal fluid irisin correlates with amyloid-β, BDNF, and cognition in Alzheimer’s disease. Alzheimers Dement (Amst). 2020;12(1):e12034.
    1. Banks WA. Leptin transport across the blood-brain barrier: implications for the cause and treatment of obesity. Curr Pharm Des. 2001;7(2):125-133.
    1. El Hayek L, Khalifeh M, Zibara V, et al. Lactate Mediates the Effects of Exercise on Learning and Memory through SIRT1-Dependent Activation of Hippocampal Brain-Derived Neurotrophic Factor (BDNF). J Neurosci. 2019;39(13):2369-2382.
    1. Horowitz AM, Fan X, Bieri G, et al. Blood factors transfer beneficial effects of exercise on neurogenesis and cognition to the aged brain. Science. 2020;369(6500):167-173.
    1. Liu TY, Xiong XQ, Ren XS, et al. FNDC5 Alleviates Hepatosteatosis by Restoring AMPK/mTOR-Mediated Autophagy, Fatty Acid Oxidation, and Lipogenesis in Mice. Diabetes. 2016;65(11):3262-3275.
    1. Li RL, Wu SS, Wu Y, et al. Irisin alleviates pressure overload-induced cardiac hypertrophy by inducing protective autophagy via mTOR-independent activation of the AMPK-ULK1 pathway. J Mol Cell Cardiol. 2018;121:242-255.
    1. Luo Y, Qiao X, Ma Y, Deng H, Xu CC, Xu L. Disordered metabolism in mice lacking irisin. Sci Rep. 2020;10(1):17368.
    1. Zhou B, Ling L, Zhang F, et al. Fibronectin Type III Domain-Containing 5 Attenuates Liver Fibrosis Via Inhibition of Hepatic Stellate Cell Activation. Cell Physiol Biochem. 2018;48(1):227-236.
    1. Zhou B, Qiu Y, Wu N, et al. FNDC5 Attenuates Oxidative Stress and NLRP3 Inflammasome Activation in Vascular Smooth Muscle Cells via Activating the AMPK-SIRT1 Signal Pathway. Oxid Med Cell Longev. 2020;2020:6384803.
    1. Li X, Fang W, Hu Y, Wang Y, Li J. Characterization of fibronectin type III domain-containing protein 5 (FNDC5) gene in chickens: cloning, tissue expression, and regulation of its expression in the muscle by fasting and cold exposure. Gene. 2015;570(2):221-229.

Source: PubMed

Sponsorzy i współpracownicy

Warunki medyczne

Interwencje lekowe

3
Subskrybuj