|fibronectin type III domain containing 5|
Fibronectin domain-containing protein 5 is a membrane protein that is the precursor of the proposed peptide hormone irisin. Irisin, a secreted from muscle in response to exercise, may mediate some beneficial effects of exercise in humans; potential for generating weight loss and blocking diabetes has been suggested. Several other research groups have reproduced these results while others have questioned the findings. One of which wrote that it is "rather unlikely that the beneficial effect of irisin observed in mice can be translated to humans". The large and growing list of independent labs that have measured human irisin in blood and have described effects on the thermogenic gene program in fat cells would seem to settle these issues.
FNDC5 was initially discovered during a genome search for fibronectin type III domains and also independently in a search for peroxisomal proteins. Irisin was found to be a cleaved version of FNDC5. Boström and coworkers named the cleaved product irisin, after the Greek messenger goddess Iris.
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, two fibronectin type III (FNIII) domains, 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.
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). The status of Met-1 and Met-76 as initiation codons is uncertain. Transcript evidence suggests the existence of the short Met-76 protein, which would produce a severely truncated irisin peptide. Although the existence of the full-length Met-1 protein has not been proven, Western blot analysis indicates the existence of a peptide with the size and immunological properties of full-length irisin in human plasma.
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. 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. 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. 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 conclusion of Boström et al. 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. Raschke et al. concluded that any function of FNDC5 and irisin in mice might be lost in humans. More than 30 reports have found irisin levels in human plasma using different, validated methods including Huh et al. 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). 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.
- Erickson HP (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.
- Courage KH. "Newly Discovered Hormone Boosts Effects of Exercise, Could Help Fend Off Diabetes". Observations. Scientific American. Retrieved January 12, 2012.
- Park A. "Brown Fat: A Fat That Helps You Lose Weight?". Health & Family. Time Magazine. Retrieved January 12, 2012.
- Reynolds G. "Exercise Hormone May Fight Obesity and Diabetes". Well. New York Times. Retrieved January 12, 2012.
- Zhang Y, Li R, Meng Y, Li S, Donelan W, Zhao Y, Qi L, Zhang M, Wang X, Cui T, Yang L-, Tang D (2013). "Irisin Stimulates Browning of White Adipocytes through Mitogen-Activated Protein Kinase p38 MAP Kinase and ERK MAP Kinase Signaling". Diabetes. doi:10.2337/db13-1106. PMID 24150604.
- Wrann CD, White JP, Salogiannnis J, Laznik-Bogoslavski D, Wu J, Ma D, Lin JD, Greenberg ME, Spiegelman BM (2013). "Exercise Induces Hippocampal BDNF through a PGC-1α/FNDC5 Pathway". Cell Metabolism 18 (5): 649. doi:10.1016/j.cmet.2013.09.008.
- 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 (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.
- Timmons JA, Baar K, Davidsen PK, Atherton PJ (2012). "Is irisin a human exercise gene?". Nature 488 (7413): E9–10; discussion E10–1. doi:10.1038/nature11364. PMID 22932392.
- 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). "Evidence against a Beneficial Effect of Irisin in Humans". In López-Lluch, Guillermo. PLoS ONE 8 (9): e73680. doi:10.1371/journal.pone.0073680. PMC 3770677. PMID 24040023.
- Teufel A, Malik N, Mukhopadhyay M, Westphal H (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.
- Ferrer-Martínez A, Ruiz-Lozano P, Chien KR (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.
- 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 (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.
- Ivanov IP, Firth AE, Michel AM, Atkins JF, Baranov PV (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.
- Huh JY, Panagiotou G, Mougios V, Brinkoetter M, Vamvini MT, Schneider BE, Mantzoros CS (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.
- Wrann CD, White JP, Salogiannnis J, Laznik-Bogoslavski D, Wu J, Ma D, Lin JD, Greenberg ME, Spiegelman BM (November 2013). "Exercise Induces Hippocampal BDNF through a PGC-1α/FNDC5 Pathway". Cell Metab. 18 (5): 649–59. doi:10.1016/j.cmet.2013.09.008. PMID 24120943.
- Fuss J, Biedermann SV, Falfán-Melgoza C, Auer MK, Zheng L, Steinle J, Hörner F, Sartorius A, Ende G, Weber-Fahr W, Gass P (November 2013). "Exercise boosts hippocampal volume by preventing early age-related gray matter loss". Hippocampus. doi:10.1002/hipo.22227. PMID 24178895. Lay summary – Nature Magazine.