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FNDC5

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Fibronectin type III domain-containing protein 5, the precursor of irisin, is a protein that is encoded by the FNDC5 gene.[1]

Fibronectin domain-containing protein 5 is a membrane protein comprising a short cytoplasmic domain, a transmembrane segment, and an ectodomain consisting of a ~100 kDa fibronectin type III (FNIII) domain. The ectodomain has been proposed to be cleaved to give a soluble peptide hormone named irisin. Boström et al [2] proposed that irisin is secreted from muscle in response to exercise, and may mediate some beneficial effects of exercise in humans; potential for generating weight loss and blocking diabetes has been suggested.[3][4][5] Several other research groups have reproduced these results[6][7][8] while others have vigorously questioned the findings.[1][9][10][11]

Discovery

FNDC5 was initially discovered in 2002 during a genome search for fibronectin type III domains[12] and also independently in a search for peroxisomal proteins.[1][13] Irisin was found to be a cleaved version of FNDC5. Boström and coworkers named the cleaved product irisin, after the Greek messenger goddess Iris.[2]

Biosynthesis and secretion

The FNDC5 gene encodes a prohormone, a single-pass type I membrane protein (human, 212 amino acids; mouse and rat, 209 amino acids) that is upregulated by muscular exercise and undergoes post-translational processing to generate irisin. The sequence of the protein includes a signal peptide, a single fibronectin type III (FNIII) domain, and a C-terminal hydrophobic domain that is probably anchored in the cell membrane. The production of irisin is similar to the shedding and release of other hormones and hormone-like polypeptides, such as EGF and TGFalpha, from transmembrane precursors. After the N-terminal signal peptide is removed, the peptide is proteolytically cleaved from the C-terminal moiety, glycosylated, and released as a hormone of 112 amino acids (in human, amino acids 32-143 of the full-length protein; in mouse and rat, amino acids 29-140) that comprises most of the FNIII repeat region. The sequence of irisin, the cleaved and secreted portion of FNDC5, is highly conserved in mammals; the human and murine sequences are identical.[2] However, the start codon of human FNDC5 is mutated to ATA, which causes it to be expressed at only 1% the level of other animals with the normal ATG start

A difference in the nucleotide sequence of human FNDC5 from that of mouse Fndc5 creates a different initiation codon, potentially generating a protein that begins at methionine-76 (Met-76). A protein initiated at Met-76 would be missing the signal peptide and would be trapped in the cytoplasm. Human FNDC5 could be initiated by the mutant ATA start codon, but Raschke et al [11] showed that this reduces the level of expression to 1% of that with the normal ATG start codon.

Function

Exercise causes increased expression in muscle of peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC-1alpha, encoded by the gene PPARGC1A), which is involved in adaptation to exercise. In mice, this causes production of the FNDC5 protein which is cleaved to give a new product irisin.[2][5] Due to its production through a mechanism initiated by muscular contraction, Pedersen and Febbraio class irisin as a myokine.[14]

Boström et al. proposed that irisin promotes the conversion of white fat to brown fat in humans which would make it a health promoting hormone.[3][4] Their proposal was based on evidence that FNDC5 induces thermogenin expression in fat cells, that overexpression of FNDC5 in the liver of mice prevented diet-induced weight gain, and that FNDC5 mRNA levels were elevated in a small number of human muscle samples after exercise.

However this proposal has been challenged by several groups.[15] Timmons et al. noted that over 1,000 genes are upregulated by exercise and examined how expression of FNDC5 was affected by exercise in ~200 humans. They found that it was upregulated only in highly active elderly humans, casting doubt on the conclusions of Boström et al.[9] Raschke et al. reported that there is a mutation in the start codon of the human gene for FNDC5 resulting in an alternative start codon, which reduced the protein level to 1% of that produced with the normal start codon when expressed in an artificial CMV-driven system. It was already known that FNDC5 used an alternative start codon together with many other expressed genes.[16] Raschke et al. concluded that any function of FNDC5 and irisin in mice might be lost in humans.[11] More than 30 reports[citation needed] have found irisin levels in human plasma using different, validated methods including Huh et al.[17] Wrann et al. show that hippocampal expression of Fndc5 in mice is induced by endurance exercise; peripheral delivery of Fndc5 to the liver by adenoviral vectors, which increases circulating irisin levels, activates a neuroprotective gene program in the brain, including expression of brain-derived neurotrophic factor (BDNF).[18][19] Endurance exercise, which is known to improve cognitive function, and the important metabolic mediators PGC-1alpha and FNDC5 are therefore linked to expression of BDNF in the brain.

However Timmons noted that his prior screen did not see any increase in FNDC5 gene expression in response to exercise.[9] Erickson noted that the original cell culture discovery used a truncated protein, missing three of the seven beta strands.[1] He also noted that the antibody used in the that study was made against a peptide in the membrane portion of FNDC5, and so should not recognize the irisin portion. Raschke et al.[11] noted that the mutant start codon of human irisin reduced its expression to 1% of that in other animals with the normal start codon; the miniscule amounts of FNDC5 and irisin in humans are too low to have any physiological role. Albrecht et al.[10] examined the ELISA's used to quantify irisin levels in blood in 50-100 followup studies, and concluded that they had strong cross-reaction to non-specific blood proteins. They questioned the validity of all of these published studies, and called irisin "a myth, rather than an exercise-inducible myokine."

Despite the pitfalls using ELISA and antibody reagents to detect irisin, the existence of human irisin has been addressed on the molecular level by targeted proteomics.[20] In Jedrychowski et al., irisin was identified and quantitated in human plasma using mass spectrometry with control peptides enriched with heavy stable isotopes as internal standards. Using parallel reaction monitoring (PRM)[21], the authors were able to show irisin is primarily translated from its non-canonical ATA start codon and circulates at ~ 3.6 ng/mL in sedentary subjects and increases to ~ 4.3 ng/mL in subjects undergoing aerobic interval training. These data clearly show that irisin exists and is regulated by exercise in human plasma.

See also

References

  1. ^ a b c d Erickson HP (Oct 2013). "Irisin and FNDC5 in retrospect: An exercise hormone or a transmembrane receptor?". Adipocyte. 2 (4): 289–293. doi:10.4161/adip.26082. PMC 3774709. PMID 24052909.
  2. ^ a b c d Boström P, Wu J, Jedrychowski MP, Korde A, Ye L, Lo JC, Rasbach KA, Boström EA, Choi JH, Long JZ, Kajimura S, Zingaretti MC, Vind BF, Tu H, Cinti S, Højlund K, Gygi SP, Spiegelman BM (Jan 2012). "A PGC1-α-dependent myokine that drives brown-fat-like development of white fat and thermogenesis". Nature. 481 (7382): 463–468. doi:10.1038/nature10777. PMC 3522098. PMID 22237023.
  3. ^ a b Courage KH. "Newly Discovered Hormone Boosts Effects of Exercise, Could Help Fend Off Diabetes". Observations. Scientific American. Retrieved January 12, 2012.
  4. ^ a b Park A (April 8, 2009). "Brown Fat: A Fat That Helps You Lose Weight?". Health & Family. Time Magazine. Retrieved January 12, 2012.
  5. ^ a b Reynolds G (January 11, 2012). "Exercise Hormone May Fight Obesity and Diabetes". Well. New York Times. Retrieved January 12, 2012.
  6. ^ Zhang Y, Li R, Meng Y, Li S, Donelan W, Zhao Y, Qi L, Zhang M, Wang X, Cui T, Yang LJ, Tang D (Feb 2014). "Irisin stimulates browning of white adipocytes through mitogen-activated protein kinase p38 MAP kinase and ERK MAP kinase signaling". Diabetes. 63 (2): 514–25. doi:10.2337/db13-1106. PMID 24150604.
  7. ^ Wrann CD, White JP, Salogiannnis J, Laznik-Bogoslavski D, Wu J, Ma D, Lin JD, Greenberg ME, Spiegelman BM (Nov 2013). "Exercise induces hippocampal BDNF through a PGC-1α/FNDC5 pathway". Cell Metabolism. 18 (5): 649–59. doi:10.1016/j.cmet.2013.09.008. PMID 24120943.
  8. ^ Wu J, Boström P, Sparks LM, Ye L, Choi JH, Giang AH, Khandekar M, Virtanen KA, Nuutila P, Schaart G, Huang K, Tu H, van Marken Lichtenbelt WD, Hoeks J, Enerbäck S, Schrauwen P, Spiegelman BM (Jul 2012). "Beige adipocytes are a distinct type of thermogenic fat cell in mouse and human". Cell. 150 (2): 366–376. doi:10.1016/j.cell.2012.05.016. PMC 3402601. PMID 22796012.
  9. ^ a b c Timmons JA, Baar K, Davidsen PK, Atherton PJ (Aug 2012). "Is irisin a human exercise gene?". Nature. 488 (7413): E9–10, discussion E10–1. doi:10.1038/nature11364. PMID 22932392.
  10. ^ a b Albrecht E, Norheim F, Thiede B, Holen T, Ohashi T, Schering L, Lee S, Brenmoehl J, Thomas S, Drevon CA, Erickson HP, Maak S (2015). "Irisin - a myth rather than an exercise-inducible myokine". Scientific Reports. 5: 8889. doi:10.1038/srep08889. PMID 25749243.
  11. ^ a b c d Raschke S, Elsen M, Gassenhuber H, Sommerfeld M, Schwahn U, Brockmann B, Jung R, Wisløff U, Tjønna AE, Raastad T, Hallén J, Norheim F, Drevon CA, Romacho T, Eckardt K, Eckel J (2013). López-Lluch G (ed.). "Evidence against a beneficial effect of irisin in humans". PloS One. 8 (9): e73680. doi:10.1371/journal.pone.0073680. PMC 3770677. PMID 24040023.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  12. ^ Teufel A, Malik N, Mukhopadhyay M, Westphal H (Sep 2002). "Frcp1 and Frcp2, two novel fibronectin type III repeat containing genes". Gene. 297 (1–2): 79–83. doi:10.1016/S0378-1119(02)00828-4. PMID 12384288.
  13. ^ Ferrer-Martínez A, Ruiz-Lozano P, Chien KR (Jun 2002). "Mouse PeP: a novel peroxisomal protein linked to myoblast differentiation and development". Developmental Dynamics. 224 (2): 154–167. doi:10.1002/dvdy.10099. PMID 12112469.
  14. ^ Pedersen BK, Febbraio MA (Oct 2008). "Muscle as an endocrine organ: focus on muscle-derived interleukin-6". Physiological Reviews. 88 (4): 1379–406. doi:10.1152/physrev.90100.2007. PMID 18923185.
  15. ^ Servick K (2015). "Biomedicine. Woes for 'exercise hormone'". Science. 347 (6228): 1299. doi:10.1126/science.347.6228.1299. PMID 25792309.
  16. ^ Ivanov IP, Firth AE, Michel AM, Atkins JF, Baranov PV (May 2011). "Identification of evolutionarily conserved non-AUG-initiated N-terminal extensions in human coding sequences". Nucleic Acids Research. 39 (10): 4220–4234. doi:10.1093/nar/gkr007. PMC 3105428. PMID 21266472.
  17. ^ Huh JY, Panagiotou G, Mougios V, Brinkoetter M, Vamvini MT, Schneider BE, Mantzoros CS (Dec 2012). "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. 61 (12): 1725–1738. doi:10.1016/j.metabol.2012.09.002. PMC 3614417. PMID 23018146.
  18. ^ Wrann CD, White JP, Salogiannnis J, Laznik-Bogoslavski D, Wu J, Ma D, Lin JD, Greenberg ME, Spiegelman BM (Nov 2013). "Exercise induces hippocampal BDNF through a PGC-1α/FNDC5 pathway". Cell Metabolism. 18 (5): 649–59. doi:10.1016/j.cmet.2013.09.008. PMID 24120943.
  19. ^ Fuss J, Biedermann SV, Falfán-Melgoza C, Auer MK, Zheng L, Steinle J, Hörner F, Sartorius A, Ende G, Weber-Fahr W, Gass P (Feb 2014). "Exercise boosts hippocampal volume by preventing early age-related gray matter loss". Hippocampus. 24 (2): 131–4. doi:10.1002/hipo.22227. PMID 24178895. {{cite journal}}: Unknown parameter |laysource= ignored (help); Unknown parameter |laysummary= ignored (help)
  20. ^ {{ Jedrychowski MP, Wrann CD, Paulo JA, Gerber KK, Szpyt J, Robinson MM, Nair KS,Gygi SP, Spiegelman BM. Detection and Quantitation of Circulating Human Irisin by Tandem Mass Spectrometry. Cell Metab. 2015 Aug 12. pii: S1550-4131(15)00392-7. doi: 10.1016/j.cmet.2015.08.001. [Epub ahead of print] PubMed PMID: 26278051.}}
  21. ^ Peterson, A. C.; Russell, J. D.; Bailey, D. J.; Westphall, M. S.; Coon, J. J. (2012). "Parallel Reaction Monitoring for High Resolution and High Mass Accuracy Quantitative, Targeted Proteomics". Molecular & Cellular Proteomics. 11 (11): 1475–1488. doi:10.1074/mcp.O112.020131. ISSN 1535-9476.{{cite journal}}: CS1 maint: unflagged free DOI (link)
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