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Kamran Ghaedi - One of the best experts on this subject based on the ideXlab platform.
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FNDC5 knockdown significantly decreased the expression of neurotrophins and their respective receptors during neural differentiation of mouse embryonic stem cells
Human Cell, 2021Co-Authors: Reihane Ebadi, Farzaneh Rabiee, Mohammad Hossein Nasr-esfahani, Dormohammad Kordi-tamandani, Kamran GhaediAbstract:Fibronectin type III domain-containing-5 (FNDC5) is a trans-membrane protein which is involved in a variety of cellular events including neural differentiation of mouse embryonic stem cells (mESCs) as its knockdown and overexpression diminishes and facilitates this process, respectively. However, downstream targets of FNDC5 in neurogenesis are still unclear. Neurotrophins including NGF, BDNF, NT-3, and NT-4 are the primary regulators of neuronal survival, growth, differentiation, and repair. These biomolecules exert their actions through binding to two different receptor families, Trk and p75NTR. In this study, considering the fact that neurotrophins and their receptors play crucial roles in neural differentiation of ESCs, we sought to evaluate whether knockdown of FNDC5 decreased neural differentiation of mESCs by affecting the neurotrophins and their receptors expression. Results showed that at neural progenitor stage, the mRNA and protein levels of BDNF, Trk, and p75NTR receptors decreased following the FNDC5 knockdown. In mature neural cells, still, the expression of Trk and p75NTR receptors at mRNA and protein levels and BDNF and NGF expression only at protein levels showed a significant decrease in FNDC5 knockdown cells compared to control groups. Taken together, our results suggest that decreased efficiency of neural differentiation following the reduction of FNDC5 expression could be attributed to decreased levels of NGF and BDNF proteins in addition to their cognate receptors.
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new insights into the cellular activities of FNDC5 irisin and its signaling pathways
Cell & Bioscience, 2020Co-Authors: Farzaneh Rabiee, Kamran Ghaedi, Mohammadhossein Nasresfahani, Liana Lachinani, Sarvenaz Ghaedi, Timothy L. MegrawAbstract:FNDC5, a well-defined myokine and also identified as an adipokine, has a critical role in modulation of metabolism and protection against obesity. These important functions are mediated by irisin, a secretory peptide produced from proteolytic processing of FNDC5. The other beneficial physiological effects of irisin are alleviation of oxidative stress, neuroprotective effects, and anti-inflammatory properties and associated anti-metastatic effects. FNDC5/irisin exerts its biological effects through several intracellular signaling pathways. The major signaling pathway is thought to be MAPK signaling pathways which are involved in neural differentiation, browning of white adipocytes, as well as osteoblast proliferation and differentiation. Other essential functions of FNDC5/irisin are mediated through additional pathways including AMPK pathway, PI3K/AKT, and STAT3/Snail. Thorough understanding of the mechanisms of irisin actions are essential in order to develop FNDC5/irisin for therapeutic purposes. In the present review, we focus on the current knowledge of the signaling pathways that elicit irisin actions.
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New insights into the cellular activities of FNDC5/Irisin and its signaling pathways.
Cell & Bioscience, 2020Co-Authors: Farzaneh Rabiee, Mohammad Hossein Nasr-esfahani, Liana Lachinani, Sarvenaz Ghaedi, Timothy L. Megraw, Kamran GhaediAbstract:FNDC5, a well-defined myokine and also identified as an adipokine, has a critical role in modulation of metabolism and protection against obesity. These important functions are mediated by irisin, a secretory peptide produced from proteolytic processing of FNDC5. The other beneficial physiological effects of irisin are alleviation of oxidative stress, neuroprotective effects, and anti-inflammatory properties and associated anti-metastatic effects. FNDC5/irisin exerts its biological effects through several intracellular signaling pathways. The major signaling pathway is thought to be MAPK signaling pathways which are involved in neural differentiation, browning of white adipocytes, as well as osteoblast proliferation and differentiation. Other essential functions of FNDC5/irisin are mediated through additional pathways including AMPK pathway, PI3K/AKT, and STAT3/Snail. Thorough understanding of the mechanisms of irisin actions are essential in order to develop FNDC5/irisin for therapeutic purposes. In the present review, we focus on the current knowledge of the signaling pathways that elicit irisin actions.
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FNDC5 knockdown induced suppression of mitochondrial integrity and significantly decreased cardiac differentiation of mouse embryonic stem cells.
Journal of Cellular Biochemistry, 2018Co-Authors: Shima Nazem, Kamran Ghaedi, Farzaneh Rabiee, Sadegh Babashah, Majid Sadeghizadeh, Mohammad Hossein Nasr-esfahaniAbstract:Fibronectin type III domain-containing 5 protein (FNDC5) is a glycosylated protein with elevated expression in high energy demanded tissues as heart, brain, and muscle. It has been shown that upregulation of FNDC5 is regulated by peroxisome proliferator-activated receptor-γ coactivator-1 alpha (PGC-1α), which is known as a master regulator of mitochondrial function and biogenesis. Also, our group indicated that FNDC5 expression increases gradually during cardiac differentiation of mouse embryonic stem cells (mESCs). In this paper, to clarify the importance of FNDC5 in cardiac differentiation, we south to knock down FNDC5 expression by generation a stably transduced mESC line that derives the expression of a short hairpin RNA (shRNA) against FNDC5 gene following doxycycline (Dox) induction. Knock-down of FNDC5 demonstrated a considerable decrease in expression of cardiac progenitor and cardiomyocyte markers. Considering the fact that mitochondria play a crucial role in cardiac differentiation of ESCs, we investigated the role of FNDC5, as a downstream target of PGC1-α, on mitochondrial indices. Results showed that expression of nuclear encoded mitochondrial genes including PGC1-α, Atp5b, Ndufb5, and SOD2 significantly decreased. Moreover, mitochondrial membrane potential (ΔΨm) and relative ATP content of cardiomyocytes decreased markedly with relative ROS level increase. Together, our results suggest that FNDC5 attenuates process of cardiac differentiation of mESCs which is associated with modulation of mitochondrial function and gene expression.
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a comparative study on the effects of high fat diet and endurance training on the pgc 1α FNDC5 irisin pathway in obese and nonobese male c57bl 6 mice
Applied Physiology Nutrition and Metabolism, 2018Co-Authors: Fatemeh Kazeminasab, Kamran Ghaedi, Sayed Mohammad Marandi, Zahra Safaeinejad, Fahimeh Esfarjani, Mohammadhossein NasresfahaniAbstract:The present study was performed to clarify how a combined exercise/diet treatment could affect the expression level of the muscle fibronectin type III domain containing 5 (FNDC5) with respect to body fat mass. Male C57BL/6 mice were divided into 2 groups including low-fat (LF) and high-fat (HF) diets for 12 weeks. Then, LF fed (nonobese) and HF fed mice (obese) were divided into the following 4 groups: HF-Exercise, HF-Sedentary, LF-Exercise, and LF-Sedentary. The exercise group exercised on a motor-driven treadmill for 45 min/day, 5 days/week for 8 weeks. Mice were sacrificed 24 h after the final exercise session. Gastrocnemius muscle and the visceral adipose tissue were excised and frozen for the assessment of proliferator-activated receptor gamma coactivator 1 alpha (Pgc-1α) and FNDC5 messenger RNA (mRNA) and protein levels. Data indicated that protein level of muscle PGC-1α was decreased in HF versus LF groups and in obese versus nonobese mice. Moreover, FNDC5 mRNA levels were increased in the muscle tissue of HF versus LF groups and in obese versus nonobese mice. Also, in the gastrocnemius skeletal muscle, protein levels of FNDC5 were significantly higher in the HF fed mice, as compared with their low-fat fed counterparts, similar to what was observed for exercised versus sedentary mice. Overall, we found that the HF diet increased FNDC5 transcript levels in the skeletal muscle, but exercise had a minimal effect on the transcript level of FNDC5, whereas endurance training increased the protein content of FNDC5 in the skeletal muscle.
Mohammad Hossein Nasr-esfahani - One of the best experts on this subject based on the ideXlab platform.
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FNDC5 knockdown significantly decreased the expression of neurotrophins and their respective receptors during neural differentiation of mouse embryonic stem cells
Human Cell, 2021Co-Authors: Reihane Ebadi, Farzaneh Rabiee, Mohammad Hossein Nasr-esfahani, Dormohammad Kordi-tamandani, Kamran GhaediAbstract:Fibronectin type III domain-containing-5 (FNDC5) is a trans-membrane protein which is involved in a variety of cellular events including neural differentiation of mouse embryonic stem cells (mESCs) as its knockdown and overexpression diminishes and facilitates this process, respectively. However, downstream targets of FNDC5 in neurogenesis are still unclear. Neurotrophins including NGF, BDNF, NT-3, and NT-4 are the primary regulators of neuronal survival, growth, differentiation, and repair. These biomolecules exert their actions through binding to two different receptor families, Trk and p75NTR. In this study, considering the fact that neurotrophins and their receptors play crucial roles in neural differentiation of ESCs, we sought to evaluate whether knockdown of FNDC5 decreased neural differentiation of mESCs by affecting the neurotrophins and their receptors expression. Results showed that at neural progenitor stage, the mRNA and protein levels of BDNF, Trk, and p75NTR receptors decreased following the FNDC5 knockdown. In mature neural cells, still, the expression of Trk and p75NTR receptors at mRNA and protein levels and BDNF and NGF expression only at protein levels showed a significant decrease in FNDC5 knockdown cells compared to control groups. Taken together, our results suggest that decreased efficiency of neural differentiation following the reduction of FNDC5 expression could be attributed to decreased levels of NGF and BDNF proteins in addition to their cognate receptors.
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New insights into the cellular activities of FNDC5/Irisin and its signaling pathways.
Cell & Bioscience, 2020Co-Authors: Farzaneh Rabiee, Mohammad Hossein Nasr-esfahani, Liana Lachinani, Sarvenaz Ghaedi, Timothy L. Megraw, Kamran GhaediAbstract:FNDC5, a well-defined myokine and also identified as an adipokine, has a critical role in modulation of metabolism and protection against obesity. These important functions are mediated by irisin, a secretory peptide produced from proteolytic processing of FNDC5. The other beneficial physiological effects of irisin are alleviation of oxidative stress, neuroprotective effects, and anti-inflammatory properties and associated anti-metastatic effects. FNDC5/irisin exerts its biological effects through several intracellular signaling pathways. The major signaling pathway is thought to be MAPK signaling pathways which are involved in neural differentiation, browning of white adipocytes, as well as osteoblast proliferation and differentiation. Other essential functions of FNDC5/irisin are mediated through additional pathways including AMPK pathway, PI3K/AKT, and STAT3/Snail. Thorough understanding of the mechanisms of irisin actions are essential in order to develop FNDC5/irisin for therapeutic purposes. In the present review, we focus on the current knowledge of the signaling pathways that elicit irisin actions.
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FNDC5 knockdown induced suppression of mitochondrial integrity and significantly decreased cardiac differentiation of mouse embryonic stem cells.
Journal of Cellular Biochemistry, 2018Co-Authors: Shima Nazem, Kamran Ghaedi, Farzaneh Rabiee, Sadegh Babashah, Majid Sadeghizadeh, Mohammad Hossein Nasr-esfahaniAbstract:Fibronectin type III domain-containing 5 protein (FNDC5) is a glycosylated protein with elevated expression in high energy demanded tissues as heart, brain, and muscle. It has been shown that upregulation of FNDC5 is regulated by peroxisome proliferator-activated receptor-γ coactivator-1 alpha (PGC-1α), which is known as a master regulator of mitochondrial function and biogenesis. Also, our group indicated that FNDC5 expression increases gradually during cardiac differentiation of mouse embryonic stem cells (mESCs). In this paper, to clarify the importance of FNDC5 in cardiac differentiation, we south to knock down FNDC5 expression by generation a stably transduced mESC line that derives the expression of a short hairpin RNA (shRNA) against FNDC5 gene following doxycycline (Dox) induction. Knock-down of FNDC5 demonstrated a considerable decrease in expression of cardiac progenitor and cardiomyocyte markers. Considering the fact that mitochondria play a crucial role in cardiac differentiation of ESCs, we investigated the role of FNDC5, as a downstream target of PGC1-α, on mitochondrial indices. Results showed that expression of nuclear encoded mitochondrial genes including PGC1-α, Atp5b, Ndufb5, and SOD2 significantly decreased. Moreover, mitochondrial membrane potential (ΔΨm) and relative ATP content of cardiomyocytes decreased markedly with relative ROS level increase. Together, our results suggest that FNDC5 attenuates process of cardiac differentiation of mESCs which is associated with modulation of mitochondrial function and gene expression.
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Zinc finger protein 521 overexpression increased transcript levels of FNDC5 in mouse embryonic stem cells.
Journal of Biosciences, 2016Co-Authors: Motahere-sadat Hashemi, Kamran Ghaedi, Alireza Shoaraye Nejati, Mohammad Hossein Nasr-esfahani, Abbas Kiani Esfahani, Maryam Peymani, Hossein BaharvandAbstract:Zinc finger protein 521 is highly expressed in brain, neural stem cells and early progenitors of the human hematopoietic cells. Zfp521 triggers the cascade of neurogenesis in mouse embryonic stem cells through inducing expression of the early neuroectodermal genes Sox1, Sox3 and Pax6. FNDC5, a precursor of Irisin has inducing effects on the expression level of brain derived neurotrophic factor in hippocampus. Therefore, it is most likely that FNDC5 may play an important role in neural differentiation. To exhibit whether the expression of this protein is under regulation with Zfp521, we overexpressed Zfp521 in a stable transformants of mESCs expressing EGFP under control of FNDC5 promoter. Increased expression of Zfp521 enhanced transcription levels of both EGFP and endogenous FNDC5. This result was confirmed by overexpression the aforementioned vectors in HEK cells and indicated that Zfp521 functions upstream of FNDC5 expression. It is most likely that Zfp521 may act through the binding to its response element on FNDC5 core promoter. Therefore it is concluding that an enhanced expression of FNDC5 in neural progenitor cells is stimulated by Zfp521 overexpression in these cells.
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FNDC5 overexpression facilitated neural differentiation of mouse embryonic stem cells
Cell Biology International, 2015Co-Authors: Mahboobeh Forouzanfar, Kamran Ghaedi, Somayeh Tanhaei, Alireza Shoaraye Nejati, Hossein Baharvand, Farzaneh Rabiee, Siamak Beheshti, Mohammad Jodeiri Farshbaf, Mohammad Hossein Nasr-esfahaniAbstract:FNDC5 has been recently recognized as a myokine which could be cleaved and secreted into blood stream. It is termed as irisin with an important role in thermogenesis and energy homeostasis. Increased expression of FNDC5 has been reported upon retinoic acid treatment during neural differentiation and its knockdown decreased neural differentiation and neurite outgrowth. This study tries to evaluate the effect of FNDC5 overexpression on rate of neural differentiation in mouse. (Thus, transduced cell line of mouse embryonic stem cell with ability to express FNDC5 under Doxycycline treatment was established. Subsequently, the effect of overexpression of FNDC5 on different stages of neural differentiation was studied). Our study showed an increase enhancement in neuronal precursor markers and mature neuron markers upon overexpression of FNDC5, concluding that FNDC5 facilitates neural differentiation. This effect might be related to increased expression of BDNF following overexpression of FNDC5. Our findings are consistent with recent studies reporting a similar role for FNDC5 in proliferation of neural cells and increase in the expression of neurotrophins like BDNF.
Hossein Baharvand - One of the best experts on this subject based on the ideXlab platform.
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Zinc finger protein 521 overexpression increased transcript levels of FNDC5 in mouse embryonic stem cells.
Journal of Biosciences, 2016Co-Authors: Motahere-sadat Hashemi, Kamran Ghaedi, Alireza Shoaraye Nejati, Mohammad Hossein Nasr-esfahani, Abbas Kiani Esfahani, Maryam Peymani, Hossein BaharvandAbstract:Zinc finger protein 521 is highly expressed in brain, neural stem cells and early progenitors of the human hematopoietic cells. Zfp521 triggers the cascade of neurogenesis in mouse embryonic stem cells through inducing expression of the early neuroectodermal genes Sox1, Sox3 and Pax6. FNDC5, a precursor of Irisin has inducing effects on the expression level of brain derived neurotrophic factor in hippocampus. Therefore, it is most likely that FNDC5 may play an important role in neural differentiation. To exhibit whether the expression of this protein is under regulation with Zfp521, we overexpressed Zfp521 in a stable transformants of mESCs expressing EGFP under control of FNDC5 promoter. Increased expression of Zfp521 enhanced transcription levels of both EGFP and endogenous FNDC5. This result was confirmed by overexpression the aforementioned vectors in HEK cells and indicated that Zfp521 functions upstream of FNDC5 expression. It is most likely that Zfp521 may act through the binding to its response element on FNDC5 core promoter. Therefore it is concluding that an enhanced expression of FNDC5 in neural progenitor cells is stimulated by Zfp521 overexpression in these cells.
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erk1 2 is a key regulator of FNDC5 and pgc1α expression during neural differentiation of mescs
Neuroscience, 2015Co-Authors: S.s. Hosseini Farahabadi, Kamran Ghaedi, Hossein Baharvand, Farzaneh Rabiee, Khadijeh Karbalaie, M Nematollahi, Ghazvini F Zadegan, Mohammadhossein NasresfahaniAbstract:Fibronectin type III domain containing 5 (FNDC5) has already been distinguished to be involved in neural differentiation. However, cellular events of FNDC5 function are still ambiguous in the nervous system. One approach to shed light on duty of this protein in the nervous system is to find its cross-talks with various signaling pathways with defined characteristics and roles. Identification of the underlying molecular mechanism which controls FNDC5 expression and switches its activity up and down enables us to find out the FNDC5 functional map in the nervous system and other human body systems. Retinoic acid (RA) is a bio-small molecule which exerts its role as a neural inducer in the neurodevelopmental process of neural tube. RA up-regulates the expression of various genes involved in neural differentiation process via two distinct pathways: the genomic and the non-genomic. Our previous study has revealed that RA induces FNDC5 expression during neural differentiation process. In this study we have evaluated our hypothesis about the non-genomic up regulation of FNDC5 expression by RA. Interestingly we have identified that there is an association between ERK signaling pathway and FNDC5 expression. Furthermore, inhibition of this pathway by PD0325901 dramatically reduced FNDC5 mRNA level, while activating the pathway up-regulated FNDC5 transcription. In addition, it has been proven that ERK1/2 modulation via RA has more significant controlling effect on FNDC5 promoter rather than bFGF. This led us to conclude that RA enhances FNDC5 expression through a non-genomic pathway via the ERK signaling pathway.
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cardiac differentiation of mouse embryonic stem cells is influenced by a ppar γ pgc 1α FNDC5 pathway during the stage of cardiac precursor cell formation
European Journal of Cell Biology, 2015Co-Authors: F. Ghazvini Zadegan, Kamran Ghaedi, Hossein Baharvand, Maryam Peymani, Seyed Mehdi Kalantar, Motahare-sadat Hashemi, Mohammadhossein NasresfahaniAbstract:Peroxisome proliferator-activated receptor (PPAR) γ co-activator 1α (PGC-1α) up-regulation induces FNDC5 expression in muscle and consequently causes browning of white adipose tissue (WAT). In addition to skeletal muscle, FNDC5 is mainly expressed in heart and brain tissues. Here, we demonstrate that FNDC5 expression increased during the process of cardiac differentiation of mouse embryonic stem cells (mESCs) similar to PGC-1α and PPARα. To testify the correlation between PGC-1α and FNDC5 in cardiac cell differentiation of mESCs, we utilized specific PPARγ agonist and antagonist in two stages of cardiac differentiation, during and post-cardiac precursor cells (CPCs) formation. Our results indicated that a reduction in PGC-1α expression, via treatment with GW9662 during CPCs formation stage, down-regulated FNDC5 transcript levels as well as mitochondrial markers which negatively influenced on the whole process of cardiac differentiation efficiency. On the other hand, increase PGC-1α expression during CPCs formation stage via rosiglitazone treatment increase FNDC5 and mitochondrial markers transcript levels which enhanced cardiac differentiation efficiency. Importantly, such alteration in PGC-1α expression at post-CPCs formation stage did not affect overall cardiac differentiation rate as expression of FNDC5 and mitochondrial markers were not significantly changed. We concluded that PPARγ agonist and antagonist induced up and down-regulation of PGC-1α and subsequently modulated the process of CPCs formation through an alteration in FNDC5 and mitochondrial markers expression.
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FNDC5 overexpression facilitated neural differentiation of mouse embryonic stem cells
Cell Biology International, 2015Co-Authors: Mahboobeh Forouzanfar, Kamran Ghaedi, Somayeh Tanhaei, Alireza Shoaraye Nejati, Hossein Baharvand, Farzaneh Rabiee, Siamak Beheshti, Mohammad Jodeiri Farshbaf, Mohammad Hossein Nasr-esfahaniAbstract:FNDC5 has been recently recognized as a myokine which could be cleaved and secreted into blood stream. It is termed as irisin with an important role in thermogenesis and energy homeostasis. Increased expression of FNDC5 has been reported upon retinoic acid treatment during neural differentiation and its knockdown decreased neural differentiation and neurite outgrowth. This study tries to evaluate the effect of FNDC5 overexpression on rate of neural differentiation in mouse. (Thus, transduced cell line of mouse embryonic stem cell with ability to express FNDC5 under Doxycycline treatment was established. Subsequently, the effect of overexpression of FNDC5 on different stages of neural differentiation was studied). Our study showed an increase enhancement in neuronal precursor markers and mature neuron markers upon overexpression of FNDC5, concluding that FNDC5 facilitates neural differentiation. This effect might be related to increased expression of BDNF following overexpression of FNDC5. Our findings are consistent with recent studies reporting a similar role for FNDC5 in proliferation of neural cells and increase in the expression of neurotrophins like BDNF.
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Enhanced expression of FNDC5 in human embryonic stem cell-derived neural cells along with relevant embryonic neural tissues.
Gene, 2015Co-Authors: Fatemeh Ahmadi Ghahrizjani, Kamran Ghaedi, Ahmad Salamian, Somayeh Tanhaei, Alireza Shoaraye Nejati, Hossein Salehi, Mohammad Nabiuni, Hossein Baharvand, Mohammad Hossein Nasr-esfahaniAbstract:Availability of human embryonic stem cells (hESCs) has enhanced the capability of basic and clinical research in the context of human neural differentiation. Derivation of neural progenitor (NP) cells from hESCs facilitates the process of human embryonic development through the generation of neuronal subtypes. We have recently indicated that fibronectin type III domain containing 5 protein (FNDC5) expression is required for appropriate neural differentiation of mouse embryonic stem cells (mESCs). Bioinformatics analyses have shown the presence of three isoforms for human FNDC5 mRNA. To differentiate which isoform of FNDC5 is involved in the process of human neural differentiation, we have used hESCs as an in vitro model for neural differentiation by retinoic acid (RA) induction. The hESC line, Royan H5, was differentiated into a neural lineage in defined adherent culture treated by RA and basic fibroblast growth factor (bFGF). We collected all cell types that included hESCs, rosette structures, and neural cells in an attempt to assess the expression of FNDC5 isoforms. There was a contiguous increase in all three FNDC5 isoforms during the neural differentiation process. Furthermore, the highest level of expression of the isoforms was significantly observed in neural cells compared to hESCs and the rosette structures known as neural precursor cells (NPCs). High expression levels of FNDC5 in human fetal brain and spinal cord tissues have suggested the involvement of this gene in neural tube development. Additional research is necessary to determine the major function of FDNC5 in this process.
Xiaoqing Xiong - One of the best experts on this subject based on the ideXlab platform.
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FNDC5 attenuates obesity induced cardiac hypertrophy by inactivating jak2 stat3 associated inflammation and oxidative stress
Journal of Translational Medicine, 2019Co-Authors: Zhi Geng, Yebo Zhou, Bing Zhou, Wen-yong Fan, Ying Tong, Xiaoqing XiongAbstract:Chronic low-grade inflammation and oxidative stress play important roles in the development of obesity-induced cardiac hypertrophy. Here, we investigated the role of Fibronectin type III domain containing 5 (FNDC5) in cardiac inflammation and oxidative stress in obesity-induced cardiac hypertrophy. Male wild-type and FNDC5−/− mice were fed normal chow or high fat diet (HFD) for 20 weeks to induce obesity, and primary cardiomyocytes and H9c2 cells treated with palmitate (PA) were used as in vitro model. The therapeutic effects of lentiviral vector-mediated FNDC5 overexpression were also examined in HFD-induced cardiac hypertrophy. High fat diet manifested significant increases in body weight and cardiac hypertrophy marker genes expression, while FNDC5 deficiency aggravated cardiac hypertrophy evidenced by increased Nppa, Nppb and Myh7 mRNA level and cardiomyocytes area, in association with enhanced cardiac inflammatory cytokines expression, oxidative stress level and JAK2/STAT3 activation in HFD-fed mice. FNDC5 deficiency in primary cardiomyocytes or FNDC5 knockdown in H9c2 cells enhanced PA-induced inflammatory responses and NOX4 expression. Exogenous FNDC5 pretreatment attenuated PA-induced cardiomyocytes hypertrophy, inflammatory cytokines up-regulation and oxidative stress in primary cardiomyocytes and H9c2 cells. FNDC5 overexpression attenuated cardiac hypertrophy as well as cardiac inflammation and oxidative stress in HFD-fed mice. FNDC5 attenuates obesity-induced cardiac hypertrophy by inactivating JAK2/STAT3 associated-cardiac inflammation and oxidative stress. The cardio-protective role of FNDC5 shed light on future therapeutic interventions in obesity and related cardiovascular complications.
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FNDC5 attenuates obesity-induced cardiac hypertrophy by inactivating JAK2/STAT3-associated inflammation and oxidative stress.
Journal of Translational Medicine, 2019Co-Authors: Zhi Geng, Yebo Zhou, Bing Zhou, Wen-yong Fan, Ying Tong, Xiaoqing XiongAbstract:Chronic low-grade inflammation and oxidative stress play important roles in the development of obesity-induced cardiac hypertrophy. Here, we investigated the role of Fibronectin type III domain containing 5 (FNDC5) in cardiac inflammation and oxidative stress in obesity-induced cardiac hypertrophy. Male wild-type and FNDC5−/− mice were fed normal chow or high fat diet (HFD) for 20 weeks to induce obesity, and primary cardiomyocytes and H9c2 cells treated with palmitate (PA) were used as in vitro model. The therapeutic effects of lentiviral vector-mediated FNDC5 overexpression were also examined in HFD-induced cardiac hypertrophy. High fat diet manifested significant increases in body weight and cardiac hypertrophy marker genes expression, while FNDC5 deficiency aggravated cardiac hypertrophy evidenced by increased Nppa, Nppb and Myh7 mRNA level and cardiomyocytes area, in association with enhanced cardiac inflammatory cytokines expression, oxidative stress level and JAK2/STAT3 activation in HFD-fed mice. FNDC5 deficiency in primary cardiomyocytes or FNDC5 knockdown in H9c2 cells enhanced PA-induced inflammatory responses and NOX4 expression. Exogenous FNDC5 pretreatment attenuated PA-induced cardiomyocytes hypertrophy, inflammatory cytokines up-regulation and oxidative stress in primary cardiomyocytes and H9c2 cells. FNDC5 overexpression attenuated cardiac hypertrophy as well as cardiac inflammation and oxidative stress in HFD-fed mice. FNDC5 attenuates obesity-induced cardiac hypertrophy by inactivating JAK2/STAT3 associated-cardiac inflammation and oxidative stress. The cardio-protective role of FNDC5 shed light on future therapeutic interventions in obesity and related cardiovascular complications.
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MOESM1 of FNDC5 attenuates obesity-induced cardiac hypertrophy by inactivating JAK2/STAT3-associated inflammation and oxidative stress
2019Co-Authors: Zhi Geng, Yebo Zhou, Bing Zhou, Wen-yong Fan, Ying Tong, Xiaoqing XiongAbstract:Additional file 1: Table S1. Primers used for real-time PCR. Figure S1. FNDC5 deficiency aggravated HFD-induced cardiac hypertrophy and enhanced cardiac TNF-α, IL-1β and IL-6 levels in mice. Figure S2. FNDC5 deficiency enhanced NLRP3 and IL18 mRNA levels in heart of mice. Figure S3. Knockdown of FNDC5 enhanced palmitate-induced inflammation and NOX4 expression in H9c2 cells. Figure S4. Effects of exogenous FNDC5 and JAK2/STAT3 inhibitor pretreatment on inflammation and oxidative stress in H9c2 cells. Figure S5. Effects of exogenous FNDC5 and JAK2/STAT3 inhibitor pretreatment on phosphorylated JAK2 and STAT3 level in H9c2 cells. Figure S6. FNDC5 overexpression attenuated phosphorylated JAK2 and STAT3 level in heart of HFD-fed mice
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FNDC5 attenuates obesity-induced cardiac hypertrophy by inactivating JAK2/STAT3-associated inflammation and oxidative stress
BMC, 2019Co-Authors: Zhi Geng, Yebo Zhou, Bing Zhou, Wen-yong Fan, Ying Tong, Xiaoqing XiongAbstract:Abstract Background Chronic low-grade inflammation and oxidative stress play important roles in the development of obesity-induced cardiac hypertrophy. Here, we investigated the role of Fibronectin type III domain containing 5 (FNDC5) in cardiac inflammation and oxidative stress in obesity-induced cardiac hypertrophy. Methods Male wild-type and FNDC5−/− mice were fed normal chow or high fat diet (HFD) for 20 weeks to induce obesity, and primary cardiomyocytes and H9c2 cells treated with palmitate (PA) were used as in vitro model. The therapeutic effects of lentiviral vector-mediated FNDC5 overexpression were also examined in HFD-induced cardiac hypertrophy. Results High fat diet manifested significant increases in body weight and cardiac hypertrophy marker genes expression, while FNDC5 deficiency aggravated cardiac hypertrophy evidenced by increased Nppa, Nppb and Myh7 mRNA level and cardiomyocytes area, in association with enhanced cardiac inflammatory cytokines expression, oxidative stress level and JAK2/STAT3 activation in HFD-fed mice. FNDC5 deficiency in primary cardiomyocytes or FNDC5 knockdown in H9c2 cells enhanced PA-induced inflammatory responses and NOX4 expression. Exogenous FNDC5 pretreatment attenuated PA-induced cardiomyocytes hypertrophy, inflammatory cytokines up-regulation and oxidative stress in primary cardiomyocytes and H9c2 cells. FNDC5 overexpression attenuated cardiac hypertrophy as well as cardiac inflammation and oxidative stress in HFD-fed mice. Conclusions FNDC5 attenuates obesity-induced cardiac hypertrophy by inactivating JAK2/STAT3 associated-cardiac inflammation and oxidative stress. The cardio-protective role of FNDC5 shed light on future therapeutic interventions in obesity and related cardiovascular complications
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FNDC5 attenuates adipose tissue inflammation and insulin resistance via ampk mediated macrophage polarization in obesity
Metabolism-clinical and Experimental, 2018Co-Authors: Xiaoqing Xiong, Juejin Wang, Yebo Zhou, Yuehua Li, Qi Chen, Feng Zhang, Zhi Geng, Bing Zhou, Yuming KangAbstract:Abstract Background Obesity-induced chronic inflammation is critical in the pathogenesis of insulin resistance, and the recruitment and proinflammatory activation of adipose tissue macrophages (ATMs) is important for the development of this process. Here, we examined the effects of fibronectin type III domain-containing 5 (FNDC5) on inflammation and insulin resistance in high-fat diet-induced obese mice. Materials and Methods Male wild-type (WT) and FNDC5−/− mice were fed with standard chow (Ctrl) or high fat diet (HFD) for 20 weeks to induce obesity and insulin resistance. Firstly, effects of FNDC5 gene deletion on obesity, insulin resistance, macrophage accumulation and polarization and adipose tissue inflammation were determined in mice. Secondly, the macrophage polarity shift was further examined with flow cytometry in isolated stromal vascular fraction (SVF). Thirdly, the effects of exogenous FNDC5 on lipopolysaccharide (LPS)-induced macrophage polarization, inflammation and the underlying signaling mechanism were investigated in RAW264.7 macrophages and primary mouse peritoneal cavity macrophages (PMs). Finally, the therapeutic effects of FNDC5 overexpression were examined in HFD-induced obese WT and FNDC5−/− mice. Results FNDC5 gene deletion aggravated obesity, insulin resistance, fat accumulation and inflammation accompanied with enhanced AMPK inhibition, macrophages recruitment and M1 polarization in mice fed with HFD. Exogenous FNDC5 inhibited LPS-induced M1 macrophage polarization and inflammatory cytokine production via AMPK phosphorylation in both RAW264.7 macrophages and PMs. FNDC5 overexpression attenuated insulin resistance, AMPK inhibition, M1 macrophage polarization and inflammatory cytokine production in adipose tissue of obese WT and FNDC5−/− mice. Conclusions FNDC5 attenuates adipose tissue inflammation and insulin resistance via AMPK-mediated macrophage polarization in HFD-induced obesity. FNDC5 plays several beneficial roles in obesity and may be used as a therapeutic regimen for preventing inflammation and insulin resistance in obesity and diabetes.
Vitazoslav Belan - One of the best experts on this subject based on the ideXlab platform.
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exercise mimicking treatment fails to increase FNDC5 mrna irisin secretion in primary human myotubes
Peptides, 2014Co-Authors: Timea Kurdiova, Miroslav Balaz, Denisa Maderova, Vitazoslav Belan, Alexander Mayer, Christian Wolfrum, Jozef Ukropec, Barbara UkropcovaAbstract:Irisin, myokine secreted by skeletal muscle, was suggested to mediate some of exercise health benefits via "browning" of white adipose tissue. However, mounting evidence contradicts the regulatory role of exercise for muscle irisin production/secretion in humans. Thus, we explored the direct effect of exercise-mimicking treatment on irisin in human primary muscle cells in vitro. Human primary muscle cell cultures were established from lean, obese prediabetic and type-2-diabetic individuals. Complex metabolic phenotyping included assessment of insulin sensitivity (euglycemic hyperinsulinemic clamp) and adiposity content&distribution (MRI&MRS). In vitro exercise-mimicking treatment (forskolin+ionomycin) was delivered in 1-h pulse/day during differentiation. FNDC5 mRNA (qRT-PCR) and secreted irisin (ELISA) were determined in cells and media. Exercise-mimicking treatment more than doubled Pgc1α mRNA in differentiated muscle cells. Nevertheless, FNDC5 mRNA was reduced by 18% and irisin in media by 20%. Moreover, Fncd5 mRNA was increased in myotubes derived from individuals with type-2-diabetes, independent on exercise-mimicking treatment. FNDC5 mRNA in cells was positively related to fasting glycemia (p=0.0001) and negatively to whole-body insulin sensitivity (p<0.05). Collectively, our data do not support the role of exercise-related signaling pathways in irisin regulation in human skeletal muscle and confirm our previous observations on increased FNDC5 expression in muscle cells from individuals with type-2-diabetes.
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effects of obesity diabetes and exercise on FNDC5 gene expression and irisin release in human skeletal muscle and adipose tissue in vivo and in vitro studies
The Journal of Physiology, 2014Co-Authors: Timea Kurdiova, Miroslav Balaz, Marek Vician, Denisa Maderova, Ladislav Valkovic, Miroslav Srbecky, Richard Imrich, Olga Kyselovicova, Miroslav Vlček, Vitazoslav BelanAbstract:Key points Considerable controversy exists regarding the role of irisin, a putative exercise-induced myokine, in human metabolism. We therefore studied irisin and its precursor FNDC5 in obesity, type 2 diabetes and exercise. Complex clinical studies combined with cell culture work revealed that FNDC5/irisin was decreased in type 2 diabetes in vivo, but not in muscle cells in vitro, indicating that diabetes-related factor(s) regulate FNDC5/irisin in vivo. Several attributes of type 2 diabetes, such as hyperglycaemia, triglyceridaemia, visceral adiposity and extramyocellular lipid deposition were negatively associated with adipose tissue FNDC5 mRNA and circulating irisin. Moreover, mimicking diabetic status in vitro by treating muscle cells with palmitate and glucose lowered FNDC5 mRNA. Neither exercise training nor an acute exercise bout modulated circulating irisin or muscle FNDC5 expression. However, the associations between intensity of habitual physical activity, muscle volume, strength, contractility and circulating irisin provide a link between irisin and positive outcomes of increased physical activity. Abstract Irisin was identified as a myokine secreted by contracting skeletal muscle, possibly mediating some exercise health benefits via ‘browning’ of white adipose tissue. However, a controversy exists concerning irisin origin, regulation and function in humans. Thus, we have explored FNDC5 gene and irisin protein in two clinical studies: (i) a cross-sectional study (effects of type 2 diabetes (T2D) in drug-naive men) and (ii) an intervention study (exercise effects in sedentary, overweight/obese individuals). Glucose tolerance and insulin sensitivity were assessed. Maximal aerobic capacity and muscle strength were measured before and after training. Body composition (magnetic resonance imaging), muscle and liver fat content (1H-magnetic resonance spectroscopy (MRS)) and in vivo muscle metabolism (32P-MRS) were determined. Skeletal muscle and subcutaneous abdominal adipose tissue samples were taken in the fasted state and during euglycaemic hyperinsulinaemia (adipose tissue) and before/after exercise training (muscle). We found that muscle FNDC5 mRNA was increased in prediabetes but not T2D. FNDC5 in adipose tissue and irisin in plasma were reduced in T2D by 40% and 50%, respectively. In contrast, T2D-derived myotubes expressed/secreted the highest levels of FNDC5/irisin. Neither hyperinsulinaemia (adipose tissue/plasma) nor exercise (muscle/plasma) affected FNDC5/irisin in vivo. Circulating irisin was positively associated with muscle mass, strength and metabolism and negatively with fasting glycaemia. Glucose and palmitate decreased FNDC5 mRNA in myotubes in vitro. We conclude that distinct patterns of FNDC5/irisin in muscle, adipose tissue and circulation, and concordant in vivo down-regulation in T2D, indicate that irisin might distinguish metabolic health and disease. Moreover, FNDC5/irisin was discordantly regulated in diabetic muscle and myotubes in vitro, suggesting that whole body factors, such as glucose and fatty acids, might be important for irisin regulation. Exercise did not affect FNDC5/irisin. However, irisin was positively linked to muscle mass, strength and metabolism, pointing to common regulatory factors and/or the potential for irisin to modify muscle phenotype.
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effects of obesity diabetes and exercise on FNDC5 gene expression and irisin release in human skeletal muscle and adipose tissue in vivo and in vitro studies
The Journal of Physiology, 2014Co-Authors: Timea Kurdiova, Miroslav Balaz, Marek Vician, Denisa Maderova, Ladislav Valkovic, Miroslav Srbecky, Richard Imrich, Olga Kyselovicova, Miroslav Vlček, Vitazoslav BelanAbstract:Irisin was identified as a myokine secreted by contracting skeletal muscle, possibly mediating some exercise health benefits via 'browning' of white adipose tissue. However, a controversy exists concerning irisin origin, regulation and function in humans. Thus, we have explored FNDC5 gene and irisin protein in two clinical studies: (i) a cross-sectional study (effects of type 2 diabetes (T2D) in drug-naive men) and (ii) an intervention study (exercise effects in sedentary, overweight/obese individuals). Glucose tolerance and insulin sensitivity were assessed. Maximal aerobic capacity and muscle strength were measured before and after training. Body composition (magnetic resonance imaging), muscle and liver fat content (1H-magnetic resonance spectroscopy (MRS)) and in vivo muscle metabolism (32P-MRS) were determined. Skeletal muscle and subcutaneous abdominal adipose tissue samples were taken in the fasted state and during euglycaemic hyperinsulinaemia (adipose tissue) and before/after exercise training (muscle). We found that muscle FNDC5 mRNA was increased in prediabetes but not T2D. FNDC5 in adipose tissue and irisin in plasma were reduced in T2D by 40% and 50%, respectively. In contrast, T2D-derived myotubes expressed/secreted the highest levels of FNDC5/irisin. Neither hyperinsulinaemia (adipose tissue/plasma) nor exercise (muscle/plasma) affected FNDC5/irisin in vivo. Circulating irisin was positively associated with muscle mass, strength and metabolism and negatively with fasting glycaemia. Glucose and palmitate decreased FNDC5 mRNA in myotubes in vitro. We conclude that distinct patterns of FNDC5/irisin in muscle, adipose tissue and circulation, and concordant in vivo down-regulation in T2D, indicate that irisin might distinguish metabolic health and disease. Moreover, FNDC5/irisin was discordantly regulated in diabetic muscle and myotubes in vitro, suggesting that whole body factors, such as glucose and fatty acids, might be important for irisin regulation. Exercise did not affect FNDC5/irisin. However, irisin was positively linked to muscle mass, strength and metabolism, pointing to common regulatory factors and/or the potential for irisin to modify muscle phenotype.
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Exercise-mimicking treatment fails to increase FNDC5 mRNA & irisin secretion in primary human myotubes.
Peptides, 2014Co-Authors: Timea Kurdiova, Miroslav Balaz, Denisa Maderova, Vitazoslav Belan, Alexander Mayer, Christian Wolfrum, Jozef Ukropec, Barbara UkropcovaAbstract:Irisin, myokine secreted by skeletal muscle, was suggested to mediate some of exercise health benefits via "browning" of white adipose tissue. However, mounting evidence contradicts the regulatory role of exercise for muscle irisin production/secretion in humans. Thus, we explored the direct effect of exercise-mimicking treatment on irisin in human primary muscle cells in vitro. Human primary muscle cell cultures were established from lean, obese prediabetic and type-2-diabetic individuals. Complex metabolic phenotyping included assessment of insulin sensitivity (euglycemic hyperinsulinemic clamp) and adiposity content&distribution (MRI&MRS). In vitro exercise-mimicking treatment (forskolin+ionomycin) was delivered in 1-h pulse/day during differentiation. FNDC5 mRNA (qRT-PCR) and secreted irisin (ELISA) were determined in cells and media. Exercise-mimicking treatment more than doubled Pgc1α mRNA in differentiated muscle cells. Nevertheless, FNDC5 mRNA was reduced by 18% and irisin in media by 20%. Moreover, Fncd5 mRNA was increased in myotubes derived from individuals with type-2-diabetes, independent on exercise-mimicking treatment. FNDC5 mRNA in cells was positively related to fasting glycemia (p=0.0001) and negatively to whole-body insulin sensitivity (p