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    Correction for Colaianni et al., The myokine irisin increases cortical bone mass. Proceedings of the National Academy of Sciences of the United States of America 10.1073/pnas.1519137112
    Bone: Irisin boosts bone mass. Holmes David Nature reviews. Endocrinology 10.1038/nrendo.2015.174
    Irisin receptor in osteocytes identified. Greenhill Claire Nature reviews. Endocrinology 10.1038/s41574-018-0151-9
    Irisin Mediates Effects on Bone and Fat via αV Integrin Receptors. Kim Hyeonwoo,Wrann Christiane D,Jedrychowski Mark,Vidoni Sara,Kitase Yukiko,Nagano Kenichi,Zhou Chenhe,Chou Joshua,Parkman Virginia-Jeni A,Novick Scott J,Strutzenberg Timothy S,Pascal Bruce D,Le Phuong T,Brooks Daniel J,Roche Alexander M,Gerber Kaitlyn K,Mattheis Laura,Chen Wenjing,Tu Hua,Bouxsein Mary L,Griffin Patrick R,Baron Roland,Rosen Clifford J,Bonewald Lynda F,Spiegelman Bruce M Cell 10.1016/j.cell.2019.06.028
    Irisin enhances osteoblast differentiation in vitro. Colaianni Graziana,Cuscito Concetta,Mongelli Teresa,Oranger Angela,Mori Giorgio,Brunetti Giacomina,Colucci Silvia,Cinti Saverio,Grano Maria International journal of endocrinology It has been recently demonstrated that exercise activity increases the expression of the myokine Irisin in skeletal muscle, which is able to drive the transition of white to brown adipocytes, likely following a phenomenon of transdifferentiation. This new evidence supports the idea that muscle can be considered an endocrine organ, given its ability to target adipose tissue by promoting energy expenditure. In accordance with these new findings, we hypothesized that Irisin is directly involved in bone metabolism, demonstrating its ability to increase the differentiation of bone marrow stromal cells into mature osteoblasts. Firstly, we confirmed that myoblasts from mice subjected to 3 weeks of free wheel running increased Irisin expression compared to nonexercised state. The conditioned media (CM) collected from myoblasts of exercised mice induced osteoblast differentiation in vitro to a greater extent than those of mice housed in resting conditions. Furthermore, the differentiated osteoblasts increased alkaline phosphatase and collagen I expression by an Irisin-dependent mechanism. Our results show, for the first time, that Irisin directly targets osteoblasts, enhancing their differentiation. This finding advances notable perspectives in future studies which could satisfy the ongoing research of exercise-mimetic therapies with anabolic action on the skeleton. 10.1155/2014/902186
    Irisin: good or bad for the bone? A new path forward after the reported discovery of irisin receptor? Anastasilakis Athanasios D,Polyzos Stergios A,Makras Polyzois,Douni Eleni,Mantzoros Christos S Metabolism: clinical and experimental 10.1016/j.metabol.2019.01.013
    Postmenopausal Osteoporosis Is Associated with Serum Chemerin and Irisin but Not with Apolipoprotein M Levels. Engin-Üstün Yaprak,Çağlayan Emel Kıyak,Göçmen Ayşe Yeşim,Polat Muhammed Fevzi Journal of menopausal medicine OBJECTIVES:The objective of this study was to describe the levels of chemerin, irisin and apolipoprotein M (apoM) in women with postmenopausal osteoporosis. METHODS:The study included 88 women with postmenopausal osteoporosis. Based on World Health Organization criteria, women with a T-score of ≤ -2.5 were defined as osteoporotic. In this case-control study, postmenopausal women with T-score > -1 were selected as controls (n = 88) and case-matched in a 1:1 ratio based on age (within 2 years) and body mass index (BMI) (within 1.0 kg/m(2)). ApoM, irisin and chemerin levels were determined by a commercially available enzyme-linked immunosorbent assay (ELISA) kit. RESULTS:There were no significant differences in age, BMI, parity, cholesterol and apoM levels between the two groups. C-reactive protein levels were significantly increased in women with osteoporosis. Serum chemerin levels (240.1 ± 46.1 vs. 261.5 ± 50.8 ng/mL) were significantly lower in the women with osteoporosis, as compared to the controls (P = 0.004). Serum irisin levels were also decreased in women with osteoporosis (0.7 ± 0.2 vs. 0.8 ± 0.2 ng/mL; P = 0.007). CONCLUSION:In the present study, osteoporosis was associated with decreased levels of circulating chemerin and irisin. These findings suggested that adipokines might play a role in the pathogenesis of osteoporosis. 10.6118/jmm.2016.22.2.76
    Low serum concentrations of Irisin are associated with increased risk of hip fracture in Chinese older women. Yan Jun,Liu Hai-Juan,Guo Wei-Chun,Yang Jian Joint bone spine OBJECTIVE:Irisin derived from muscle in response to exercise may be the molecular entity responsible for muscle wasting-osteoporosis connectivity in the elderly. The objective of the study was to determine whether serum Irisin (sIrisin) provides information on hip fracture prediction which were independent of bone mineral density (BMD) and the fracture risk assessment tool (FRAX) algorithm. METHODS:This study enrolled 160 older women (ages, 70-90y) with minimal trauma hip fractures (MTHFs) and 160 age-matched women without fracture serving as controls. Clinical features, BMD and bone turnover markers including sIrisin levels were measured after fracture within 2 days as baseline. RESULTS:sIrisin levels were significantly lower (361.5±140.0ng/mL vs 478.5±159.6ng/mL, P<0.001) in cases than controls. After multivariate analysis, sIrisin remained as an independent variable of BMD, which explained 17.8% of femoral neck BMD and 22.5% of lumbar spine BMD, respectively. The odds ratio (OR) of MTHFs comparing the lowest (<320.1ng/mL) to highest (>524.5ng/mL) quartiles was 1.95 (95% CI 1.23-3.79, P<0.05) for sIrisin. Adjustment for age, body mass index, time since menopause and exercise ≥30min/day yielded similar results, and BMD of femoral neck also did not change these associations. Taking FRAX score into account attenuated the association somewhat: OR of hip fracture was 1.81 (95% CI 1.26-3.49, P<0.05) in first versus fourth quartile of sIrisin. There was a negative gradient of risk by decreasing quartile in sIrisin. CONCLUSIONS:Low concentrations of sIrisin in older women were independently associated with increased risk of hip fractures when adjusted for BMD or FRAX score. 10.1016/j.jbspin.2017.03.011
    Evaluation of circulating irisin levels in healthy young individuals after a single 100,000 IU vitamin D dose. Cavalier Étienne,Mismetti Valentine,Souberbielle Jean-Claude Annales d'endocrinologie Irisin is a newly discovered hormone produced by the muscle. This hormone is involved in glucose metabolism, muscle strength and energy expenditure. As vitamin D is also known as a key player in that field, we aimed to see if a single dose of 100,000 IU of vitamin D would modify circulating levels of irisin in 29 young adults. Irisin was determined with the Phoenix Elisa assay at day 0, day 3, day 7 day 15 and day 28 after the loading dose. If we observed a significant increase in 25(OH)D levels (from 19.8±8.4 ng/mL to 33.0±8.5 ng/mL), irisin levels remained constant throughout the study (median 104.5 ng/mL, with values ranging from 69.9 to 390.9 ng/mL). Interestingly, one subject presented irisin values that were three times higher than all the others. 10.1016/j.ando.2014.05.005
    Irisin promotes osteoblast proliferation and differentiation via activating the MAP kinase signaling pathways. Qiao Xiaoyong,Yong Qiao Xiao,Nie Ying,Ma Yaxian,Xian Ma Ya,Chen Yan,Cheng Ran,Yin Weiyao,Yao Yinrg Wei,Hu Ying,Xu Wenming,Ming Xu Wen,Xu Liangzhi,Zhi Xu Liang Scientific reports Physical exercise is able to improve skeletal health. However, the mechanisms are poorly known. Irisin, a novel exercise-induced myokine, secreted by skeletal muscle in response to exercise, have been shown to mediate beneficial effects of exercise in many disorders. In the current study, we demonstrated that irisin promotes osteoblast proliferation, and increases the expression of osteoblastic transcription regulators, such as Runt-related transcription factor-2, osterix/sp7; and osteoblast differentiation markers, including alkaline phosphatase, collagen type 1 alpha-1, osteocalcin, and osteopontin in vitro. Irisin also increase ALP activity and calcium deposition in cultured osteoblast. These osteogenic effects were mediated by activating the p38 mitogen-activated protein kinase (p-p38 MAPK) and extracellular signal-regulated kinase (ERK). Inhibition of p38 MAPK by SB023580 or pERK by U0126 abolished the proliferation and up-regulatory effects of irisin on Runx2 expression and ALP activity. Together our observation suggest that irisin directly targets osteoblast, promoting osteoblast proliferation and differentiation via activating P38/ERK MAP kinase signaling cascades in vitro. Whether irisin can be utilized as the therapeutic agents for osteopenia and osteoporosis is worth to be further pursued. 10.1038/srep18732
    Roles of Irisin in the Linkage from Muscle to Bone During Mechanical Unloading in Mice. Kawao Naoyuki,Moritake Akihiro,Tatsumi Kohei,Kaji Hiroshi Calcified tissue international Mechanical unloading induces disuse muscle atrophy and bone loss, but the details in mechanism involved in those pathophysiological conditions are not fully understood. Interaction between muscle and bone has been recently noted. Here, we investigated the roles of humoral factors linking muscle to bone during mechanical unloading using mice with hindlimb unloading (HU) and sciatic neurectomy (SNX). HU and SNX reduced muscle volume surrounding the tibia, tissue weights of soleus and gastrocnemius muscle, and trabecular bone mineral density (BMD) in the tibia of mice. Among humoral factors linking muscle to bone, HU and SNX reduced fibronectin type III domain-containing 5 (FNDC5) mRNA levels in the soleus muscle of mice. Simple regression analysis revealed that FNDC5 mRNA levels in the soleus muscle were positively related to trabecular BMD in the tibia of control and HU mice as well as sham and SNX mice. Moreover, FNDC5 mRNA levels were negatively correlated with receptor activator of nuclear factor-κB ligand (RANKL) mRNA levels in the tibia of control and HU mice. Irisin, a product of FNDC5, suppressed osteoclast formation from mouse bone marrow cells and RANKL mRNA levels in primary osteoblasts. FNDC5 mRNA levels elevated by fluid shear stress were antagonized by bone morphogenetic protein (BMP) and phosphatidylinositol 3-kinase (PI3K) signaling inhibitors in myoblastic C2C12 cells. In conclusion, the present study first showed that mechanical unloading reduces irisin expression in the skeletal muscle of mice presumably through BMP and PI3K pathways. Irisin might be involved in muscle/bone relationships regulated by mechanical stress in mice. 10.1007/s00223-018-0387-3
    Irisin levels are lower in young amenorrheic athletes compared with eumenorrheic athletes and non-athletes and are associated with bone density and strength estimates. Singhal Vibha,Lawson Elizabeth A,Ackerman Kathryn E,Fazeli Pouneh K,Clarke Hannah,Lee Hang,Eddy Kamryn,Marengi Dean A,Derrico Nicholas P,Bouxsein Mary L,Misra Madhusmita PloS one Irisin and FGF21 are novel hormones implicated in the "browning" of white fat, thermogenesis, and energy homeostasis. However, there are no data regarding these hormones in amenorrheic athletes (AA) (a chronic energy deficit state) compared with eumenorrheic athletes (EA) and non-athletes. We hypothesized that irisin and FGF21 would be low in AA, an adaptive response to low energy stores. Furthermore, because (i) brown fat has positive effects on bone, and (ii) irisin and FGF21 may directly impact bone, we hypothesized that bone density, structure and strength would be positively associated with these hormones in athletes and non-athletes. To test our hypotheses, we studied 85 females, 14-21 years [38 AA, 24 EA and 23 non-athletes (NA)]. Fasting serum irisin and FGF21 were measured. Body composition and bone density were assessed using dual energy X-ray absorptiometry, bone microarchitecture using high resolution peripheral quantitative CT, strength estimates using finite element analysis, resting energy expenditure (REE) using indirect calorimetry and time spent exercising/week by history. Subjects did not differ for pubertal stage. Fat mass was lowest in AA. AA had lower irisin and FGF21 than EA and NA, even after controlling for fat and lean mass. Across subjects, irisin was positively associated with REE and bone density Z-scores, volumetric bone mineral density (total and trabecular), stiffness and failure load. FGF21 was negatively associated with hours/week of exercise and cortical porosity, and positively with fat mass and cortical volumetric bone density. Associations of irisin (but not FGF21) with bone parameters persisted after controlling for potential confounders. In conclusion, irisin and FGF21 are low in AA, and irisin (but not FGF21) is independently associated with bone density and strength in athletes. 10.1371/journal.pone.0100218
    Effects of Swimming Exercise on Serum Irisin and Bone FNDC5 in Rat Models of High-Fat Diet-Induced Osteoporosis. Kang Yun-Seok,Kim Jae-Cheol,Kim Jeong-Seok,Kim Sang Hyun Journal of sports science & medicine This study aimed to investigate the expression of PGC-1α/FNDC5/irisin induced by attenuation of high-fat diet (HFD)-induced bone accrual and determine whether swimming exercise could improve attenuating bone accrual through this mechanism. Eight-week-old Sprague-Dawley rats were divided into two groups for the first 8 weeks: CD, control diet (n = 10); and HFD, high-fat diet (n = 20). HFD-fed rats were again divided into two groups for further 8 weeks treatment: HFD (n = 10) and HFD with swimming exercise (HEx, n = 10). During this time, the CD group continuously fed the normal diet. Throughout the 16 weeks study period, the rats were weighed once every week. Samples were collected for analysis after last 8 weeks of treatment in the 16 weeks. Morphological and structural changes of the femur and tibial bone were observed using micro-CT, and Osteocalcin, CTX-1 and irisin levels in the blood were measured by enzyme-linked immunosorbent assay. The expression of IL-1, β-catenin, FNDC5 and PGC-1α, in the femur were evaluated by immunohistochemistry. Eight weeks of HFD increased body weight and epididymal fat mass and decreased bone mineral density (BMD). Subsequent 8 weeks of swimming exercise improved obesity, BMD, bone microstructure, and bone metabolic factors in the HEx group. The irisin levels in the blood and the expressions of FNDC5 and PGC-1α in the bone were significantly lower in the HFD group than in the CD group, but elevated in the HEx group than in the HFD group. Swimming exercise is effective in improving obesity-worsened bone health and increases blood irisin and bone PGC-1α and FNDC5 levels.
    Circulating irisin is associated with osteoporotic fractures in postmenopausal women with low bone mass but is not affected by either teriparatide or denosumab treatment for 3 months. Anastasilakis A D,Polyzos S A,Makras P,Gkiomisi A,Bisbinas I,Katsarou A,Filippaios A,Mantzoros C S Osteoporosis international : a journal established as result of cooperation between the European Foundation for Osteoporosis and the National Osteoporosis Foundation of the USA UNLABELLED:In vitro data suggest that myokine irisin may affect bone metabolism by promoting osteoblast differentiation while inhibiting osteoclast differentiation. In this study, circulating irisin levels were associated with previous osteoporotic fractures but not with bone mass and were not affected by denosumab or teriparatide treatment for 3 months. INTRODUCTION:This study aimed to evaluate predictors of circulating irisin in postmenopausal women with low bone mass and to assess a potential effect of denosumab or teriparatide treatment for 3 months. METHODS:Serum samples for irisin measurement were obtained from (a) postmenopausal women with low bone mass (lumbar spinal [LS] or femoral neck [FN] bone mineral density [BMD] T-score ≤-2.0) and their age-matched controls at baseline and 3 months after denosumab (Dmab) injection (Dmab group, n = 50; Dmab control group, n = 25) and (b) women with more severe disease (LS or FN BMD T-score ≤-2.8) and their age-matched controls at the above-mentioned time points after teriparatide (TPTD) initiation (TPTD group, n = 25; TPTD control group, n = 25). RESULTS:At baseline, irisin levels were inversely correlated with age (partial coefficient (r p ) = -0.24; p = 0.009), parathyroid hormone (PTH) (r p  = -0.30; p = 0.001), and creatinine (r p  = -0.23; p = 0.016) in univariate analysis, and were lower in women with (n = 26; 41.6 ± 2.7 ng/dL) than without previous osteoporotic fracture(s) (n = 99; 51.0 ± 1.6 ng/dL; p = 0.007). In multiple linear regression, previous osteoporotic fracture(s) and PTH were independently negatively associated with irisin [p = 0.04, CI -16.1 to -0.4 and p = 0.002, CI -0.3 to -0.07, respectively], but only the association with PTH remained after controlling for creatinine levels. Serum irisin levels were not different between women with or without low bone mass and were not affected by either Dmab or TPTD treatment for 3 months. CONCLUSIONS:Circulating irisin levels were associated with previous osteoporotic fracture(s); whether this association is independent or is due to confounding by lower muscle mass, potentially reflected by lower creatinine levels, remains to be fully clarified. 10.1007/s00198-014-2673-x
    The immunomodulatory role of irisin on osteogenesis via AMPK-mediated macrophage polarization. Ye Wenbin,Wang Jiangze,Lin Dasheng,Ding Zhenqi International journal of biological macromolecules Bone healing is thought to be closely related to macrophages. Irisin, a cleaved hormone-like myokine, is well known to participate in immunoregulation and regulates bone metabolism. However, whether irisin could influence osteogenesis by affecting macrophage polarization is remain unknown. Here, the present study aims to investigate the potential immunomodulatory role of irisin on macrophages polarization and its subsequent impact on osteogenesis. We demonstrated that irisin increased cell viability without toxic effect in both Raw264.7 macrophages and MC3T3-E1 cells. Furthermore, irisin treatment polarized M0 and M1 macrophages towards M2 phenotype, with increased expression of CD206-APC, ARG-1 and TGF-β1, and decreased expression of CD86-PE and TNF-α. In addition, the direct co-cultured test of Raw264.7 macrophages and pre-osteoblastic MC3T3-E1 cells showed that irisin-treated M0 and M1 macrophages promoted osteogenesis with obvious formation of mineralized particles. Interestingly, irisin exposure robustly activated AMPK-α signaling, as manifested by increased expression of phosphorylated AMPK-α. Knockdown of AMPK-α by siRNA significantly suppressed the phosphorylation of AMPK-α, abrogated irisin-induced polarization of M2 phenotype, and inhibited the osteogenic ability of Raw264.7 macrophages. Taken together, our findings showed that irisin-induced M2 polarization enhanced osteogenesis in osteoblasts, and this effect might be associated with activation of AMPK. 10.1016/j.ijbiomac.2019.12.028
    Irisin is associated with osteoporotic fractures independently of bone mineral density, body composition or daily physical activity. Palermo Andrea,Strollo Rocky,Maddaloni Ernesto,Tuccinardi Dario,D'Onofrio Luca,Briganti Silvia Irina,Defeudis Giuseppe,De Pascalis Mariangela,Lazzaro Maria Concetta,Colleluori Georgia,Manfrini Silvia,Pozzilli Paolo,Napoli Nicola Clinical endocrinology BACKGROUND:Although there is an evidence of correlation between irisin and osteoporotic fractures, previous studies have not elucidated the relationship between irisin and either lean or fat mass. The main aim of this study is to investigate the relationship between irisin and body composition in postmenopausal women with osteoporosis and the impact of irisin levels on fragility vertebral fractures. METHODS:In this cross-sectional study, 36 overweight subjects affected by at least one vertebral osteoporotic fracture confirmed by an X-ray vertebral morphometry and 36 overweight nonosteoporotic subjects were enrolled. Serum irisin levels were measured using an irisin competitive ELISA. We evaluated lumbar spine and hip BMD and body composition using dual energy X-ray absorptiometry. To measure and monitor daily physical activity, each subject wore an armband for approximately 72 h. RESULTS:No significant correlations were found between irisin and BMD at any site and between irisin with either lean or fat mass. Serum levels of irisin were not correlated with the daily physical activity. Serum irisin levels were lower in subjects with previous osteoporotic fractures than in controls (P = 0·032), and the difference in irisin levels remained significant after adjustment for creatinine (P = 0·037), vitamin D (P = 0·046), lean mass (P = 0·02), lumbar BMD (P = 0·023) and femoral BMD (P = 0·032). CONCLUSION:Our data confirm an inverse correlation between irisin levels and vertebral fragility fractures, but no significant correlation was found with BMD or lean mass. Irisin may play a protective role on bone health independent of BMD but further studies are needed to clarify the relationship between irisin and bone metabolism. 10.1111/cen.12672
    The myokine irisin increases cortical bone mass. Colaianni Graziana,Cuscito Concetta,Mongelli Teresa,Pignataro Paolo,Buccoliero Cinzia,Liu Peng,Lu Ping,Sartini Loris,Di Comite Mariasevera,Mori Giorgio,Di Benedetto Adriana,Brunetti Giacomina,Yuen Tony,Sun Li,Reseland Janne E,Colucci Silvia,New Maria I,Zaidi Mone,Cinti Saverio,Grano Maria Proceedings of the National Academy of Sciences of the United States of America It is unclear how physical activity stimulates new bone synthesis. We explored whether irisin, a newly discovered myokine released upon physical activity, displays anabolic actions on the skeleton. Young male mice were injected with vehicle or recombinant irisin (r-irisin) at a low cumulative weekly dose of 100 µg kg(-1). We observed significant increases in cortical bone mass and strength, notably in cortical tissue mineral density, periosteal circumference, polar moment of inertia, and bending strength. This anabolic action was mediated primarily through the stimulation of bone formation, but with parallel notable reductions in osteoclast numbers. The trabecular compartment of the same bones was spared, as were vertebrae from the same mice. Higher irisin doses (3,500 µg kg(-1) per week) cause browning of adipose tissue; this was not seen with low-dose r-irisin. Expectedly, low-dose r-irisin modulated the skeletal genes, Opn and Sost, but not Ucp1 or Pparγ expression in white adipose tissue. In bone marrow stromal cell cultures, r-irisin rapidly phosphorylated Erk, and up-regulated Atf4, Runx2, Osx, Lrp5, β-catenin, Alp, and Col1a1; this is consistent with a direct receptor-mediated action to stimulate osteogenesis. We also noted that, although the irisin precursor Fndc5 was expressed abundantly in skeletal muscle, other sites, such as bone and brain, also expressed Fndc5, albeit at low levels. Furthermore, muscle fibers from r-irisin-injected mice displayed enhanced Fndc5 positivity, and irisin induced Fdnc5 mRNA expression in cultured myoblasts. Our data therefore highlight a previously unknown action of the myokine irisin, which may be the molecular entity responsible for muscle-bone connectivity. 10.1073/pnas.1516622112
    Role of Irisin on the bone-muscle functional unit. Colaianni Graziana,Grano Maria BoneKEy reports Irisin was originally recognized as a hormone-like myokine secreted as a product of fibronectin type III domain containing 5 from skeletal muscle in response to exercise both in mice and humans. The first role attributed to Irisin was its ability to induce trans-differentiation of white adipose tissue into brown, but we recently demonstrated that Irisin also has a central role in the control of bone mass, even at lower concentration than required to induce the browning response. Considering how physical exercise is important for the development of an efficient load-bearing skeleton, we can now consider this myokine as one of the molecules responsible for the positive correlation between exercise and healthy bone, linking to the well-established relationship between muscle and bone. Recombinant Irisin (r-Irisin), administered at low dose in young mice, increases cortical bone mineral density and positively modifies bone geometry. Irisin exerts its effect prevalently on osteoblast lineage by enhancing differentiation and activity of bone-forming cells, through the increase in activating transcription factor 4 expression. Low-dose r-Irisin also increases osteopontin and decreases sclerostin synthesis but did not affect Uncoupling protein 1 expression in white adipose tissue, whose upregulation is known to cause browning of fat, when Irisin is administered at a higher dose. These findings offer an explanation to the positive outcome on the skeleton triggered by skeletal muscle during physical activity and prove that the bone tissue is more sensitive than the adipose tissue to the Irisin action. 10.1038/bonekey.2015.134
    Irisin prevents and restores bone loss and muscle atrophy in hind-limb suspended mice. Colaianni Graziana,Mongelli Teresa,Cuscito Concetta,Pignataro Paolo,Lippo Luciana,Spiro Giovanna,Notarnicola Angela,Severi Ilenia,Passeri Giovanni,Mori Giorgio,Brunetti Giacomina,Moretti Biagio,Tarantino Umberto,Colucci Silvia C,Reseland Janne E,Vettor Roberto,Cinti Saverio,Grano Maria Scientific reports We previously showed that Irisin, a myokine released from skeletal muscle after physical exercise, plays a central role in the control of bone mass. Here we report that treatment with recombinant Irisin prevented bone loss in hind-limb suspended mice when administered during suspension (preventive protocol) and induced recovery of bone mass when mice were injected after bone loss due to a suspension period of 4 weeks (curative protocol). MicroCT analysis of femurs showed that r-Irisin preserved both cortical and trabecular bone mineral density, and prevented a dramatic decrease of the trabecular bone volume fraction. Moreover, r-Irisin protected against muscle mass decline in the hind-limb suspended mice, and maintained the fiber cross-sectional area. Notably, the decrease of myosin type II expression in unloaded mice was completely prevented by r-Irisin administration. Our data reveal for the first time that Irisin retrieves disuse-induced bone loss and muscle atrophy. These findings may lead to development of an Irisin-based therapy for elderly immobile osteoporotic and physically disable patients, and might represent a countermeasure for astronauts subjected to microgravity-induced bone and muscle losses. 10.1038/s41598-017-02557-8
    The Irisin Hormone Profile and Expression in Human Bone Tissue in the Bone Healing Process in Patients. Serbest Sancar,Tiftikçi Uğur,Tosun Hacı Bayram,Kısa Üçler Medical science monitor : international medical journal of experimental and clinical research BACKGROUND Whether or not there is a relationship between the newly-discovered irisin hormone and bone healing is not yet known. The aim of this study was to investigate what effect irisin hormone has on the bone healing process. MATERIAL AND METHODS The study included 21 adult patients with a diagnosed fracture of the lower extremity (femur or tibia). Informed consent was obtained from all the patients. A total of four venous blood samples were taken from the patients: before fracture stabilization, then postoperatively on days 1, 10, and 60. In patients with femoral neck fracture who had hip prosthesis applied, bone tissue samples were taken from the removed femur head and irisin was determined immunohistochemically in muscle biopsies taken from the same patients. RESULTS In analysis, it was revealed that the mean value of irisin 60 days after operation is significantly higher than the values of irisin before operation, 1 day after operation, and 15 day after operation (p<0.001, p<0.001, p<0.001, respectively). Intense staining was observed in compact bone tissue, muscle tissue, and in hypertrophic vascular endothelium within the Havers canal. CONCLUSIONS The level of irisin hormone increased in the bone union process and affects fracture healing due to irisin receptors in human bone tissue. 10.12659/msm.906293
    Exercise-induced irisin in bone and systemic irisin administration reveal new regulatory mechanisms of bone metabolism. Zhang Jin,Valverde Paloma,Zhu Xiaofang,Murray Dana,Wu Yuwei,Yu Liming,Jiang Hua,Dard Michel M,Huang Jin,Xu Zhiwei,Tu Qisheng,Chen Jake Bone research Irisin is a polypeptide hormone derived from the proteolytic cleavage of fibronectin-type III domain-containing 5 (FNDC5) protein. Once released to circulation upon exercise or cold exposure, irisin stimulates browning of white adipose tissue (WAT) and uncoupling protein 1 (UCP1) expression, leading to an increase in total body energy expenditure by augmented UCP1-mediated thermogenesis. It is currently unknown whether irisin is secreted by bone upon exercise or whether it regulates bone metabolism . In this study, we found that 2 weeks of voluntary wheel-running exercise induced high levels of FNDC5 messenger RNA as well as FNDC5/irisin protein expression in murine bone tissues. Increased immunoreactivity due to exercise-induced FNDC5/irisin expression was detected in different regions of exercised femoral bones, including growth plate, trabecular bone, cortical bone, articular cartilage, and bone-tendon interface. Exercise also increased expression of osteogenic markers in bone and that of UCP1 in WAT, and led to bodyweight loss. Irisin intraperitoneal (IP) administration resulted in increased trabecular and cortical bone thickness and osteoblasts numbers, and concurrently induced UCP1 expression in subcutaneous WAT. Lentiviral FNDC5 IP administration increased cortical bone thickness. studies in bone cells revealed irisin increases osteoblastogenesis and mineralization, and inhibits receptor activator of nuclear factor-kB ligand (RANKL)-induced osteoclastogenesis. Taken together, our findings show that voluntary exercise increases irisin production in bone, and that an increase in circulating irisin levels enhances osteogenesis in mice. 10.1038/boneres.2016.56
    Irisin levels correlate with bone mineral density in soccer players. Colaianni G,Notarnicola A,Sanesi L,Brunetti G,Lippo L,Celi M,Moretti L,Pesce V,Vicenti G,Moretti B,Colucci S,Grano M Journal of biological regulators and homeostatic agents Irisin, a novel myokine produced in response to physical exercise by skeletal muscle, displays anabolic effect on bone and can improve the bone-loss-induced osteoporosis in hind limb suspended mice. It is well known that muscles positively impact the skeleton and in different sports, including soccer, total body bone mineral density (TB-BMD) is elevated. Therefore, we have investigated the correlation between irisin serum levels and total and bone sub-regional BMD in soccer players never studied before. In this study, Caucasian football players of Bari team have been enrolled. Their sera were collected to measure by ELISA kit irisin levels and by dual-energy X-ray absorptiometry (DEXA) analysis measurements of BMD (g • cm−2) in the whole body and different bone sub-regions (head, arms, legs, ribs, dorsal vertebrae, lumbar vertebrae, pelvis) were performed. The BMC (g) was measured in the whole body. By means of Pearson’s (R) and Cohen’s (d) coefficient we investigated the linear association between the irisin serum levels and BMD. In soccer players, we have found a positive correlation between irisin and TB-BMD as demonstrated by the values of Pearson and Cohen’s (d) coefficient. Furthermore, linear association was detected between irisin and BMD of different bone-site such as right arm, lumbar vertebrae and head. A positive trend was also observed analyzing circulating levels of irisin and bone mineral content as well as total Z-score. In conclusion, we have demonstrated the correlation between irisin and total or bone sub-regional BMD in soccer players for the first time, an additional systemic effect of the “sport-hormone” defined myokine.
    Delivery vehicle of muscle-derived irisin based on silk/calcium silicate/sodium alginate composite scaffold for bone regeneration. Xin Xianzhen,Wu Jiannan,Zheng Ao,Jiao Delong,Liu Yang,Cao Lingyan,Jiang Xinquan International journal of nanomedicine Background:Irisin is a cytokine produced by skeletal muscle and usually plays a pivotal role in inducing fat browning and regulating energy expenditure. In recent years, it was found that irisin might be the molecular entity responsible for muscle-bone connectivity and is useful in osteogenesis induction. Materials and methods:To study its effect on bone regeneration, we developed silk/calcium silicate/sodium alginate (SCS) composite scaffold based on an interpenetrating network hydrogel containing silk fibroin, calcium silicate, sodium alginate. Then we loaded irisin on the SCS before coating it with polyvinyl alcohol (PVA). The SCS/P scaffold was physically characterized and some in vitro and in vivo experiments were carried out to evaluate the scaffold effect on bone regeneration. Results:The SCS/P scaffold was showed a porous sponge structure pursuant to scanning electron microscopy analysis. The release kinetics assay demonstrated that irisin was stably released from the irisin-loaded hybrid system (i/SCS/P system) to 50% within 7 days. Moreover, osteoinductive studies using bone marrow stem cells (BMSCs) in vitro exhibited the i/SCS/P system improved the activity of alkaline phosphatase (ALP) and enhanced the expression levels of a series of osteogenic markers containing Runx-2, ALP, BMP2, Osterix, OCN, and OPN. Alizarin red staining also demonstrated the promotion of osteogenesis induced by i/SCS/P scaffolds. In addition, in vivo studies showed that increased bone regeneration with better mineralization and higher quality was found during the repair of rat calvarial defects through utilizing the i/SCS/P system. Conclusion:These data provided strong evidence that the composite i/SCS/P would be a promising substitute for bone tissue engineering. 10.2147/IJN.S193544
    Irisin promotes proliferation but inhibits differentiation in osteoclast precursor cells. Ma Yaxian,Qiao Xiaoyong,Zeng Rujun,Cheng Ran,Zhang Jun,Luo Yunyao,Nie Ying,Hu Ying,Yang Zhilan,Zhang Jing,Liu Lin,Xu Wenming,Xu Charles C,Xu Liangzhi FASEB journal : official publication of the Federation of American Societies for Experimental Biology The receptor activator of NF-κB ligand-induced osteoclast differentiation has a critical role in the process of bone metabolism. Overactivation of osteoclastogenesis may result in a series of diseases. Irisin, a novel myokine, which was first reported in 2012, has been proposed to mediate the beneficial metabolic effects of exercise. Studies have demonstrated that irisin targets osteoblasts by promoting osteoblast proliferation and differentiation; however, the underlying mechanism regarding the effect of irisin on osteoclasts remains elusive. Using 2 types of osteoclast precursor cells, RAW264.7 cells and mouse bone marrow monocytes, we showed that irisin promoted osteoclast precursor cell proliferation but inhibited osteoclast differentiation. Irisin down-regulated the expression of osteoclast differentiation marker genes, including receptor activators of NF-κB, nuclear factor of activated T cells, cytoplasmic 1, cathepsin K, and tartrate-resistant acid phosphatase (TRAP), as well as decreasing the number of TRAP-positive multinucleated cells and hydroxyapatite resorption pits. Furthermore, we showed that irisin suppressed the NF-κB signaling pathway, but activated the p38 and JNK signaling pathways. In the presence of an inhibitor of p38 and JNK, irisin-induced promotion of RAW264.7 cell proliferation was attenuated. However, irisin-induced inhibition of osteoclast differentiation was not affected by either the p38 or JNK signaling pathway. Our study suggested the direct effect of irisin on osteoclastogenesis and revealed the mechanism responsible for the therapeutic potential of irisin in bone metabolism disease.-Ma, Y., Qiao, X., Zeng, R., Cheng, R., Zhang, J., Luo, Y., Nie, Y., Hu, Y., Yang, Z., Zhang, J., Liu, L., Xu, W., Xu, C. C., Xu, L. Irisin promotes proliferation but inhibits differentiation in osteoclast precursor cells. 10.1096/fj.201700983RR
    Irisin and musculoskeletal health. Colaianni Graziana,Cinti Saverio,Colucci Silvia,Grano Maria Annals of the New York Academy of Sciences Irisin is a hormone-like myokine produced in abundance by skeletal muscle in response to exercise, both in mice and humans. Once released into the circulation, irisin acts on white adipocytes to induce the browning response and subsequently activates nonshivering thermogenesis. We have examined the premise that irisin produced during exercise may subserve further functions in the musculoskeletal system. We review evidence for its possible skeletal effects, including the central role that irisin plays in the control of bone mass, with positive effects on cortical mineral density and geometry in mice. We also review the autocrine effects of irisin in skeletal muscle, in which it upregulates the expression of its precursor (FNDC5). Since loss of bone and muscle mass occurs with aging, immobility, and several metabolic diseases, future studies exploring the efficacy of irisin in restoring bone and reversing muscle wasting could be important to establishing irisin as a molecule that combines beneficial effects for treating osteoporosis and muscular atrophy. If the results from mice were confirmed in human studies, an irisin-based therapy could be developed for physically disabled or bedridden patients. 10.1111/nyas.13345
    Irisin serum levels are positively correlated with bone mineral status in a population of healthy children. Colaianni Graziana,Faienza Maria F,Sanesi Lorenzo,Brunetti Giacomina,Pignataro Patrizia,Lippo Luciana,Bortolotti Sara,Storlino Giuseppina,Piacente Laura,D'Amato Gabriele,Colucci Silvia,Grano Maria Pediatric research BACKGROUND:Irisin is a myokine secreted by skeletal muscle during physical activity. Irisin treatment increased cortical bone mineral density (BMD) in young healthy mice and restored bone and muscle mass loss in a mouse model of disuse-induced osteoporosis and muscular atrophy. In humans, Irisin was positively correlated with BMD in young athletes. Considering that the bone mass reached during childhood is one of the most important determinants of lifelong skeletal health, we sought to determine if Irisin levels were correlated with bone mineral status in children. METHODS:Irisin and bone metabolic markers were quantified in sera and bone mineral status was evaluated by quantitative ultrasound in a population of 34 healthy children (9.82 ± 3.2 years). RESULTS:We found that Irisin levels were positively correlated with the amplitude-dependent speed of sound Z-score (r = 0.305; p < 0.001), bone transmission time Z-score (r = 0.375; p < 0.001) and osteocalcin (r = 0.370; p < 0.001), and negatively with Dickkopf WNT Signaling Pathway Inhibitor 1 (r = -0.274; p < 0.001). CONCLUSION:In a regression analysis model, Irisin was one of the determinants of bone mineral status to a greater extent than bone alkaline phosphatase and parathyroid hormone, indicating that Irisin might be considered as one of the bone formation markers during childhood. 10.1038/s41390-019-0278-y
    Irisin as a regulator of bone and glucose metabolism. Briganti Silvia I,Gaspa Gianluigi,Tabacco Gaia,Naciu Anda M,Cesareo Roberto,Manfrini Silvia,Palermo Andrea Minerva endocrinologica In humans, irisin is produced mainly by skeletal muscle in response to physical activity. It has been demonstrated that irisin plays a pivotal role in inducing fat browning and regulating energy expenditure. New findings from various studies conducted in both animals and humans suggest that irisin can affect bone and glucose metabolism. In particular, irisin is able to increase bone cortical mass by stimulating the osteoblast pathways, and irisin levels are inversely correlated with the incidence of fragility fractures among postmenopausal women affected by osteoporosis. Most available evidence shows that irisin significantly influences glucose and energy homeostasis. Indeed, higher irisin concentrations are inversely correlated with type 2 diabetes. Unfortunately, contradictory findings exist concerning the role of irisin in humans, and most of the human studies that have analyzed interactions between bone health, glucose metabolism, and irisin have several limitations; therefore, their results must be interpreted with caution. The purpose of this narrative review is mainly to describe the effects of irisin on glucose and bone metabolism. 10.23736/S0391-1977.17.02779-1
    The effect of His-tag and point mutation on the activity of irisin on MC3T3-E1 cells. Zeng Rujun,Ma Yaxian,Qiao Xiaoyong,Zhang Jun,Luo Yunyao,Li Sicong,Liu Ling,Xu Liangzhi Bioscience trends Irisin is a myokine secreted from the cleavage of fibronectin type III domain-containing protein 5 (FNDC5) and has an effect on bone formation. There are limited studies about the structure of irisin and its functional unit. In order to clarify the candidate domain responsible for irisin action, we constructed several irisin variants and tested their influence on the proliferation and osteogenesis of MC3T3-E1 cells. On the one hand, His-tag was added to the N terminal or C terminal of irisin. On the other hand, the flexible region or salt bridge site were chosen as the candidate for point mutation. Alkaline phosphatase (ALP), Runt related transcription factor 2 (Runx2) and collagen type I alpha 1 (COL1α1) were chosen to test the differentiation efficiency. We found point mutation on flexible regions, Glu-57 and Ile-107, and adding His-tag on the C-terminal of irisin did affect its action. The osteogenic potential of irisin E57K, irisin I107F and irisin decreased about 90.1%, 88.8% and 96.6% activity of recombinant-irisin (r-irisin) (P < 0.05), respectively. Point mutation on the salt bridge, Arg-75, partly decreased the effect of irisin (45 ± 11.3% of r-irisin) (P < 0.05). N-terminal His-tag showed almost no effect (93.5 ± 25.7% of r-irisin) (P = 0.658). This study suggested that the flexible region of residues 55-58 and 106-108, and C-terminal of irisin are vital for its activity. Disrupting the dimerization of irisin might result in a partly reduced effect on cell differentiation. 10.5582/bst.2018.01207
    Lower circulating irisin in middle-aged and older adults with osteoporosis: a systematic review and meta-analysis. Zhou Kunyan,Qiao Xiaoyong,Cai Yitong,Li Ailin,Shan Dan Menopause (New York, N.Y.) OBJECTIVE:Osteoporosis has imposed a heavy socioeconomic burden worldwide, especially in postmenopausal women. As a newly found protein, irisin has an important physiological role in bone metabolism. This meta-analysis intends to identify the association between circulating irisin levels and osteoporosis. METHODS:This meta-analysis was conducted following the Meta-analysis of Observational Studies in Epidemiology (MOOSE) guideline. A comprehensive search of five databases was performed from inception to January 2019. Studies with original date on middle-aged and older participants were included. Data were analyzed according to study characteristics and heterogeneity between studies. The quality of each study and the presence of publication bias were assessed by Newcastle-Ottawa score (NOS) and normal quantile plot. RESULTS:Seven studies, with a total of 1,018 participants, conducted in four countries, were included. Six of them were identified as high-quality research. Five studies included postmenopausal women, and two studies included both men and women. Possible publication bias was found in the analysis of irisin and osteoporosis. Pooled analysis indicated decreased irisin levels in osteoporotic participants (mean difference -87.91, 95% CI, -92.56 to -83.25). Subgroup analysis revealed an even lower level of irisin in postmenopausal women and in participants with a history of fractures. Analysis on associations between irisin and femoral neck or lumbar spine bone mineral density showed a weak positive correlation. CONCLUSIONS:The findings of this analysis suggested that circulating irisin levels were decreased in middle-aged and older participants with osteoporosis. Irisin was positively correlated with bone mineral density. 10.1097/GME.0000000000001388
    Lower circulating irisin in middle-aged and older adults with osteoporosis: a systematic review and meta-analysis. Zhou Kunyan,Qiao Xiaoyong,Cai Yitong,Li Ailin,Shan Dan Menopause (New York, N.Y.) OBJECTIVE:Osteoporosis has imposed a heavy socioeconomic burden worldwide, especially in postmenopausal women. As a newly found protein, irisin has an important physiological role in bone metabolism. This meta-analysis intends to identify the association between circulating irisin levels and osteoporosis. METHODS:This meta-analysis was conducted following the Meta-analysis of Observational Studies in Epidemiology (MOOSE) guideline. A comprehensive search of five databases was performed from inception to January 2019. Studies with original date on middle-aged and older participants were included. Data were analyzed according to study characteristics and heterogeneity between studies. The quality of each study and the presence of publication bias were assessed by Newcastle-Ottawa score (NOS) and normal quantile plot. RESULTS:Seven studies, with a total of 1,018 participants, conducted in four countries, were included. Six of them were identified as high-quality research. Five studies included postmenopausal women, and two studies included both men and women. Possible publication bias was found in the analysis of irisin and osteoporosis. Pooled analysis indicated decreased irisin levels in osteoporotic participants (mean difference -87.91, 95% CI, -92.56 to -83.25). Subgroup analysis revealed an even lower level of irisin in postmenopausal women and in participants with a history of fractures. Analysis on associations between irisin and femoral neck or lumbar spine bone mineral density showed a weak positive correlation. CONCLUSIONS:The findings of this analysis suggested that circulating irisin levels were decreased in middle-aged and older participants with osteoporosis. Irisin was positively correlated with bone mineral density. 10.1097/GME.0000000000001388
    Association of Plasma Irisin with Bone Mineral Density in a Large Chinese Population Using an Extreme Sampling Design. Wu Long-Fei,Zhu Dong-Cheng,Tang Chang-Hua,Ge Bing,Shi Ju,Wang Bing-Hua,Lu Yi-Hua,He Pei,Wang Wen-Yu,Lu Si-Qi,Zhong Jiao,Zhou Xu,Zhu Kan,Ji Wen,Gao Hong-Qin,Gu Hong-Bo,Mo Xing-Bo,Lu Xin,Zhang Lei,Zhang Yong-Hong,Deng Fei-Yan,Lei Shu-Feng Calcified tissue international Irisin, a myokine produced by skeletal muscle in response to physical exercise, promotes trans-differentiation of white adipose tissue into brown adipose tissue. Recent evidences suggested that irisin also plays an important role in the control of bone metabolism. This study aimed to ascertain the relationship between plasma irisin and bone mineral density (BMD) in Chinese population by adoption of an extreme sampling method. Based on a large and screened Chinese elderly population (N = 6308), two subgroups with extremely high and low hip BMD were selected for discovery (N = 80, high vs. low BMD = 44:36) and validation (N = 60, high vs. low BMD = 30:30), respectively. Plasma irisin, P1NP, and β-CTx were measured using commercially available ELISA kits. Other metabolic parameters (e.g., blood glucose, total cholesterol and triglycerides) were collected. Student's t test and Spearman correlation analyses were conducted in SPSS. Significant difference was discovered for plasma irisin between females and age-matched males (N = 80, male vs. female = 42:38, P = 0.002). The plasma irisin levels were significantly higher in high BMD subjects than in low BMD subjects, which was observed in both discovery (P = 0.012) and validation samples (P = 0.022). However, such observation was limited to males only. Further correlation analyses in males showed that plasma irisin was correlated with BMD (r = 0.362, P = 0.025) and triglyceride (r = - 0.354, P = 0.032). Plasma irisin levels were associated with hip BMD in Chinese elderly men. This study represented the first effort of investigating the relationship of plasma irisin and BMD in elderly population. The positive correlation between plasma irisin and BMD hints intrinsic communication between muscle and bone. 10.1007/s00223-018-0415-3
    The bone anabolic effects of irisin are through preferential stimulation of aerobic glycolysis. Zhang Dongdong,Bae ChuHyun,Lee Junghak,Lee Jiho,Jin Zeyu,Kang Myeongmo,Cho Young Suk,Kim Jeong-Han,Lee Weontae,Lim Sung-Kil Bone Irisin, a recently identified hormone secreted by skeletal muscle in response to exercise, exhibits anabolic effects on the skeleton primarily through the stimulation of bone formation. However, the mechanism underlying the irisin-stimulated anabolic response remains largely unknown. To uncover the underlying mechanism, we biosynthesized recombinant irisin (r-irisin) using an Escherichia coli expression system and used it to treat several osteoblast cell types. Our synthesized r-irisin could promote proliferation and differentiation of osteoblasts as evidenced by enhanced expression of osteoblast-specific transcriptional factors, including Runt-related transcription factor-2 (Runx2), Oster (Osx), as well as early osteoblastic differentiation markers such as alkaline phosphatase (Alp) and collagen type I alpha 1 (Col1a1). Furthermore, we showed that the promotion of r-irisin on the proliferation and differentiation of osteoblast lineage cells are preferentially through aerobic glycolysis, as indicated by the enhanced abundance of representative enzymes such as lactate dehydrogenase A (LDHA) and pyruvate dehydrogenase kinase 1 (PDK1), together with increased lactate levels. Suppression of r-irisin-mediated aerobic glycolysis with Dichloroacetate blunted its anabolic effects. The favorite of the aerobic glycolysis after r-irisin treatment was then confirmed in primary calvarial cells by metabolic analysis using gas chromatography-mass spectrometry. Thus, our results suggest that the anabolic actions of r-irisin on the regulation of osteoblast lineage cells are preferentially through aerobic glycolysis, which may help to develop new irisin-based bone anabolic agents. 10.1016/j.bone.2018.05.013
    Irisin Mediates Effects on Bone and Fat via αV Integrin Receptors. Kim Hyeonwoo,Wrann Christiane D,Jedrychowski Mark,Vidoni Sara,Kitase Yukiko,Nagano Kenichi,Zhou Chenhe,Chou Joshua,Parkman Virginia-Jeni A,Novick Scott J,Strutzenberg Timothy S,Pascal Bruce D,Le Phuong T,Brooks Daniel J,Roche Alexander M,Gerber Kaitlyn K,Mattheis Laura,Chen Wenjing,Tu Hua,Bouxsein Mary L,Griffin Patrick R,Baron Roland,Rosen Clifford J,Bonewald Lynda F,Spiegelman Bruce M Cell Irisin is secreted by muscle, increases with exercise, and mediates certain favorable effects of physical activity. In particular, irisin has been shown to have beneficial effects in adipose tissues, brain, and bone. However, the skeletal response to exercise is less clear, and the receptor for irisin has not been identified. Here we show that irisin binds to proteins of the αV class of integrins, and biophysical studies identify interacting surfaces between irisin and αV/β5 integrin. Chemical inhibition of the αV integrins blocks signaling and function by irisin in osteocytes and fat cells. Irisin increases both osteocytic survival and production of sclerostin, a local modulator of bone remodeling. Genetic ablation of FNDC5 (or irisin) completely blocks osteocytic osteolysis induced by ovariectomy, preventing bone loss and supporting an important role of irisin in skeletal remodeling. Identification of the irisin receptor should greatly facilitate our understanding of irisin's function in exercise and human health. 10.1016/j.cell.2018.10.025
    Variations in Irisin, Bone Mineral Density, Bone Mineral Content, and Body Composition After Laparoscopic Bariatric Procedures in Obese Adults. Lu Chunting,Li Zejian,Yang Jing,Feng Lie,Wang Cunchuan,Shi Qiping Journal of clinical densitometry : the official journal of the International Society for Clinical Densitometry INTRODUCTION:This study was aimed to assess irisin levels in obesity (OB) and T2DM individuals and investigate the dynamic changes of irisin, bone mineral density (BMD), bone mineral content, and body composition in 19 OB patients after laparoscopic bariatric procedures, and also to evaluate the correlation of irisin, with BMD and body composition. METHODS:Forty-five OB, 20 T2DM, and 20 healthy adults had been recruited. Levels of irisin were measured in all subjects. Metabolic characteristics were obtained from OB and T2DM patients. Nineteen patients were randomly assigned to be received Roux-en-Y gastric bypass (LRYGB) or laparoscopic sleeve gastrectomy (LSG) procedure and to be completed 6-month follow-up. Irisin, BMD, bone mineral content, and body composition were measured at each visit. RESULTS:Significantly higher circulating irisin levels were measured in the OB group compared with T2DM and control groups. FINS, C-P, HOMA-IR, FBCI, HBCI, ALT, AST, and UA levels of OB were significantly higher than those of T2DM patients. While FBG and HbA1c of the OB were significantly lower than T2DM group. There were significant differences among circulating irisin, BMD, and body composition after laparoscopic bariatric surgery. Levels of irisin were decreased after operations including both LRYGB and LSG surgery compared with preoperation. At each time point (1, 3, and 6 months) of postoperation, there was no significant difference in percentage of total weight loss between LSG and LRYGB group. The positive correlation of irisin levels with total BMD, muscle, and fat masses were found during 6-month follow-up after surgery. CONCLUSIONS:The levels of irisin were higher in OB patients. There were positive correlations of irisin levels with total BMD, muscle, and fat masses during 6-month follow-up after surgery. Irisin may be involved in the occurrence and development of obese and it is related to BMD and body composition. Both LRYGB and LSG operations could decrease the circulating levels of irisin. 10.1016/j.jocd.2019.05.002
    Irisin and Bone: From Preclinical Studies to the Evaluation of Its Circulating Levels in Different Populations of Human Subjects. Colaianni Graziana,Sanesi Lorenzo,Storlino Giuseppina,Brunetti Giacomina,Colucci Silvia,Grano Maria Cells Almost four years after the discovery of the anabolic action of irisin on bone in mice, ample clinical evidence is emerging in support of its additional physiological relevance in human bone. Irisin inversely correlates with sclerostin levels in adults with prediabetes and with vertebral fragility fractures in post-menopausal women. Furthermore, in athletes we observed a positive correlation between irisin and bone mineral density at different anatomical sites. Our group also described a positive association between serum irisin and bone status in healthy children and multivariate regression analysis showed that irisin is a stronger determinant of bone mineral status than bone alkaline phosphatase. In children with type 1 diabetes mellitus, serum irisin concentrations are positively associated with bone quality and with glycemic control following continuous subcutaneous insulin infusion. Additionally, our in vitro studies suggest the existence of a negative interplay between PTH and irisin biology and these results were also supported by the observation that post-menopausal women with primary hyperparathyroidism have lower levels of irisin compared to matched controls. In this review, we will focus on recent findings about circulating level of irisin in different populations of human subjects and its correlation with their bone status. 10.3390/cells8050451
    Irisin pretreatment ameliorates intestinal ischemia/reperfusion injury in mice through activation of the Nrf2 pathway. Du Juan,Fan Xin,Yang Bo,Chen Ye,Liu Ke-Xuan,Zhou Jun International immunopharmacology Intestinal ischemia/reperfusion (I/R) injury is a serious clinical event that may induce intestinal mucosal injury, whose major underlying mechanisms include reactive oxygen species (ROS) generation, release of inflammatory mediators and induction of apoptosis. Irisin is considered an agent with potent protection against many pathological injures. The aim of this study was to investigate the protective effect of irisin pretreatment on intestinal injury and explore its underlying mechanisms in a mouse model of intestinal I/R injury as well as a cell model (IEC-6 cell) of hypoxia/reoxygenation (H/R). The results showed that irisin pretreatment ameliorated I/R and H/R-induced injury in vivo and in vitro. In addition, irisin reduced the levels of tumor necrosis factor (TNF)-α, interleukin(IL)-1β and interleukin(IL)-6 in the intestine. Compared with the I/R group, irisin pretreatment effectively reduced malondialdehyde (MDA) and myeloperoxidase (MPO) levels, but increased superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) activities in the intestine, and significantly reduced oxidative stress. Furthermore, irisin pretreatment downregulated Bax and cleaved Caspase-3 at the protein level, and increased Bcl-2 protein amounts, significantly reducing apoptosis in the intestine of I/R mice. Moreover, both in vivo and in vitro results showed that irisin pretreatment significantly upregulated nuclear factor (erythroid-derived 2)-like 2 (Nrf2) protein. Meanwhile, Nrf2 siRNA treatment partially abrogated the protective effects of irisin pretreatment on H/R induced cellular damage, inflammatory response, oxidative stress, and apoptosis in IEC-6 cells. These findings suggest that irisin pretreatment improves I/R-induced intestinal inflammatory response, reduces oxidative stress and inhibits apoptosis, which could be, at least partially, associated with Nrf2 pathway activation. 10.1016/j.intimp.2019.05.011
    Irisin Prevents Disuse-Induced Osteocyte Apoptosis. Storlino Giuseppina,Colaianni Graziana,Sanesi Lorenzo,Lippo Luciana,Brunetti Giacomina,Errede Mariella,Colucci Silvia,Passeri Giovanni,Grano Maria Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research Previous results showed that intermittently administered irisin improves bone mass in normal mice and prevents the development of disuse-induced osteoporosis and muscular atrophy in hindlimb-suspended mice, a murine model able to mimic the absence of mechanical loading. A recent study showed that irisin increases survival of osteocytes acting through integrin αV/β5 receptors. To better understand the action of irisin on these cells, we investigated the downstream signaling cascades in osteocyte-like cells (MLO-Y4) treated with recombinant irisin (rec-irisin) in vitro and we analyzed survival of osteocytes and caspase activation in cortical bone of osteoporotic mice treated with rec-irisin in vivo. Our results revealed that rec-irisin activated the MAP kinases Erk1 and Erk2 and increased the expression of the transcription factor Atf4 (2.5-fold, p < .05) through an Erk-dependent pathway in osteocytes. Some key genes expressed by MLO-Y4 cells were modulated by long-term irisin treatment, either continuously administered or given with intermittent short pulses. Interestingly, Sost mRNA was severely downregulated only upon intermittent irisin administration (10-fold, p < .001). Furthermore, rec-irisin upregulated Tfam mRNA (fourfold, p < .05) and Bcl2/Bax ratio (twofold, p < .05) in MLO-Y4 cells. By detecting caspase-9 and caspase-3, we also found that rec-irisin inhibited apoptosis induced by hydrogen peroxide and dexamethasone, respectively. In cortical bone of unloading C57BL6 mice treated with vehicle (unload-veh), irisin prevented disuse-induced reduction of viable osteocytes (+30% versus unload-veh, p < .05) and increase of empty lacunae (+110% versus unload-veh, p < .05), as well as caspase-9 (threefold, p < .05) and caspase-3 (twofold, p < .05) activations. Our findings revealed underlying mechanisms of irisin action on osteocytes, which increases their functions and exerts anti-apoptotic effects, confirming that mechanosensor cells of bone are sensitive to the exercise-mimetic myokine irisin. © 2019 American Society for Bone and Mineral Research. 10.1002/jbmr.3944