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Rong P, Mu Y, Wang M, Chen L, Liu F, Jin Y, Feng W, Zhou K, Liang H, Wang HY, Chen S. Targeting IGF1 to alleviate obesity through regulating energy expenditure and fat deposition. SCIENCE CHINA. LIFE SCIENCES 2025; 68:1662-1675. [PMID: 39843847 DOI: 10.1007/s11427-024-2768-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/13/2024] [Accepted: 10/31/2024] [Indexed: 01/24/2025]
Abstract
Insulin-like growth factor 1 (IGF1) is a regulator of both cellular hypertrophy and lipogenesis, which are two key processes for pathogenesis of obesity. However, the in vivo role of IGF1 in the development of obesity remains unclear. Here, we show that IGF1 expression is increased in adipose tissue in obese human patients and animal models. Elevation of IGF1 is associated with increased lipogenic gene expression and decreased energy expenditure. Genetic down-regulation of IGF1 normalizes lipogenic gene expression, restores aberrant energy metabolism and alleviates obese phenotype of a genetic mouse model with IGF1-hypersecretion. Importantly, genetic down-regulation of IGF1 exerts similar effects on development of diet-induced obesity. Furthermore, berberine that is an AMP-activated protein kinase (AMPK) activator in medicinal herbs inhibits IGF1 secretion, decreases lipogenic gene expression and alleviates diet-induced adiposity. Collectively, our findings demonstrate that hypersecretion of IGF1 is a critical factor for the development of obesity and can be targeted using AMPK activators to alleviate obesity.
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Affiliation(s)
- Ping Rong
- State Key Laboratory of Pharmaceutical Biotechnology, Department of Endocrinology, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Model Animal Research Center, Nanjing University, Nanjing, 210061, China
- MOE Key Laboratory of Model Animal for Disease Study, Model Animal Research Center, School of Medicine, Nanjing University, Nanjing, 210061, China
| | - Yinqiu Mu
- State Key Laboratory of Pharmaceutical Biotechnology, Department of Endocrinology, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Model Animal Research Center, Nanjing University, Nanjing, 210061, China
- MOE Key Laboratory of Model Animal for Disease Study, Model Animal Research Center, School of Medicine, Nanjing University, Nanjing, 210061, China
| | - Meiqin Wang
- State Key Laboratory of Pharmaceutical Biotechnology, Department of Endocrinology, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Model Animal Research Center, Nanjing University, Nanjing, 210061, China
- MOE Key Laboratory of Model Animal for Disease Study, Model Animal Research Center, School of Medicine, Nanjing University, Nanjing, 210061, China
| | - Liang Chen
- College of Life Sciences, Anhui Medical University, Hefei, 230032, China
| | - Fangtong Liu
- State Key Laboratory of Pharmaceutical Biotechnology, Department of Endocrinology, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Model Animal Research Center, Nanjing University, Nanjing, 210061, China
- MOE Key Laboratory of Model Animal for Disease Study, Model Animal Research Center, School of Medicine, Nanjing University, Nanjing, 210061, China
| | - Yuxin Jin
- State Key Laboratory of Pharmaceutical Biotechnology, Department of Endocrinology, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Model Animal Research Center, Nanjing University, Nanjing, 210061, China
- MOE Key Laboratory of Model Animal for Disease Study, Model Animal Research Center, School of Medicine, Nanjing University, Nanjing, 210061, China
| | - Weikuan Feng
- State Key Laboratory of Pharmaceutical Biotechnology, Department of Endocrinology, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Model Animal Research Center, Nanjing University, Nanjing, 210061, China
- MOE Key Laboratory of Model Animal for Disease Study, Model Animal Research Center, School of Medicine, Nanjing University, Nanjing, 210061, China
| | - Kun Zhou
- State Key Laboratory of Pharmaceutical Biotechnology, Department of Endocrinology, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Model Animal Research Center, Nanjing University, Nanjing, 210061, China
- MOE Key Laboratory of Model Animal for Disease Study, Model Animal Research Center, School of Medicine, Nanjing University, Nanjing, 210061, China
| | - Hui Liang
- Department of General Surgery, First Affiliated Hospital, Nanjing Medical University, Nanjing, 210029, China
| | - Hong-Yu Wang
- State Key Laboratory of Pharmaceutical Biotechnology, Department of Endocrinology, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Model Animal Research Center, Nanjing University, Nanjing, 210061, China.
- MOE Key Laboratory of Model Animal for Disease Study, Model Animal Research Center, School of Medicine, Nanjing University, Nanjing, 210061, China.
| | - Shuai Chen
- State Key Laboratory of Pharmaceutical Biotechnology, Department of Endocrinology, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Model Animal Research Center, Nanjing University, Nanjing, 210061, China.
- MOE Key Laboratory of Model Animal for Disease Study, Model Animal Research Center, School of Medicine, Nanjing University, Nanjing, 210061, China.
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Reda GK, Ndunguru SF, Csernus B, Knop R, Lugata JK, Szabó C, Czeglédi L, Lendvai ÁZ. Dietary restriction reveals sex-specific expression of the mTOR pathway genes in Japanese quails. Sci Rep 2024; 14:8314. [PMID: 38594358 PMCID: PMC11004124 DOI: 10.1038/s41598-024-58487-9] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2023] [Accepted: 03/29/2024] [Indexed: 04/11/2024] Open
Abstract
Limited resources affect an organism's physiology through the conserved metabolic pathway, the mechanistic target of rapamycin (mTOR). Males and females often react differently to nutritional limitation, but whether it leads to differential mTOR pathway expression remains unknown. Recently, we found that dietary restriction (DR) induced significant changes in the expression of mTOR pathway genes in female Japanese quails (Coturnix japonica). We simultaneously exposed 32 male and female Japanese quails to either 20%, 30%, 40% restriction or ad libitum feeding for 14 days and determined the expression of six key genes of the mTOR pathway in the liver to investigate sex differences in the expression patterns. We found that DR significantly reduced body mass, albeit the effect was milder in males compared to females. We observed sex-specific liver gene expression. DR downregulated mTOR expression more in females than in males. Under moderate DR, ATG9A and RPS6K1 expressions were increased more in males than in females. Like females, body mass in males was correlated positively with mTOR and IGF1, but negatively with ATG9A and RS6K1 expressions. Our findings highlight that sexes may cope with nutritional deficits differently and emphasise the importance of considering sexual differences in studies of dietary restriction.
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Affiliation(s)
- Gebrehaweria K Reda
- Department of Animal Science, Faculty of Agricultural and Food Sciences and Environmental Management, Institute of Animal Science, Biotechnology and Nature Conservation, University of Debrecen, 4032, Debrecen, Hungary.
- Doctoral School of Animal Science, University of Debrecen, 4032, Debrecen, Hungary.
- Department of Evolutionary Zoology and Human Biology, University of Debrecen, 4032, Debrecen, Hungary.
| | - Sawadi F Ndunguru
- Department of Animal Science, Faculty of Agricultural and Food Sciences and Environmental Management, Institute of Animal Science, Biotechnology and Nature Conservation, University of Debrecen, 4032, Debrecen, Hungary
- Doctoral School of Animal Science, University of Debrecen, 4032, Debrecen, Hungary
- Department of Evolutionary Zoology and Human Biology, University of Debrecen, 4032, Debrecen, Hungary
| | - Brigitta Csernus
- Department of Evolutionary Zoology and Human Biology, University of Debrecen, 4032, Debrecen, Hungary
| | - Renáta Knop
- Department of Animal Science, Faculty of Agricultural and Food Sciences and Environmental Management, Institute of Animal Science, Biotechnology and Nature Conservation, University of Debrecen, 4032, Debrecen, Hungary
| | - James K Lugata
- Doctoral School of Animal Science, University of Debrecen, 4032, Debrecen, Hungary
- Department of Animal Nutrition and Physiology, Faculty of Agriculture and Food Sciences and Environmental Management, University of Debrecen, 4032, Debrecen, Hungary
| | - Csaba Szabó
- Department of Animal Nutrition and Physiology, Faculty of Agriculture and Food Sciences and Environmental Management, University of Debrecen, 4032, Debrecen, Hungary
| | - Levente Czeglédi
- Department of Animal Science, Faculty of Agricultural and Food Sciences and Environmental Management, Institute of Animal Science, Biotechnology and Nature Conservation, University of Debrecen, 4032, Debrecen, Hungary
| | - Ádám Z Lendvai
- Department of Evolutionary Zoology and Human Biology, University of Debrecen, 4032, Debrecen, Hungary
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Bersin TV, Cordova KL, Journey ML, Beckman BR, Lema SC. Food deprivation reduces sensitivity of liver Igf1 synthesis pathways to growth hormone in juvenile gopher rockfish (Sebastes carnatus). Gen Comp Endocrinol 2024; 346:114404. [PMID: 37940008 DOI: 10.1016/j.ygcen.2023.114404] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/25/2023] [Revised: 10/19/2023] [Accepted: 11/03/2023] [Indexed: 11/10/2023]
Abstract
Growth hormone (Gh) regulates growth in part by stimulating the liver to synthesize and release insulin-like growth factor-1 (Igf1), which then promotes somatic growth. However, for fish experiencing food limitation, elevated blood Gh can occur even with low circulating Igf1 and slow growth, suggesting that nutritional stress can alter the sensitivity of liver Igf1 synthesis pathways to Gh. Here, we examined how recent feeding experience affected Gh regulation of liver Igf1 synthesis pathways in juvenile gopher rockfish (Sebastes carnatus) to illuminate mechanisms underlying the nutritional modulation of Igf1 production. Juvenile gopher rockfish were maintained under conditions of feeding or complete food deprivation (fasting) for 14 d and then treated with recombinant sea bream (Sparus aurata) Gh or saline control. Gh upregulated hepatic igf1 mRNA levels in fed fish but not in fasted fish. The liver of fasted rockfish also showed a lower relative abundance of gene transcripts encoding teleost Gh receptors 1 (ghr1) and 2 (ghr2), as well as reduced protein levels of phosphorylated janus tyrosine kinase 2 (pJak2) and signal transducer and activator of transcription 5 (pStat5), which function to induce igf1 gene transcription following Gh binding to Gh receptors. Relative hepatic mRNA levels for suppressors of cytokine signaling (Socs) genes socs2, socs3a, and socs3b were also lower in fasted rockfish. Socs2 can suppress Gh activation of Jak2/Stat5, and fasting-related variation in socs expression may reflect modulated inhibitory control of igf1 gene transcription. Fasted rockfish also had elevated liver mRNA abundances for lipolytic hormone-sensitive lipase 1 (hsl1) and Igf binding proteins igfbp1a, -1b and -3a, reduced liver mRNAs encoding igfbp2b and an Igfbp acid labile subunit-like (igfals) gene, and higher transcript abundances for Igf1 receptors igf1ra and igf1rb in skeletal muscle. Together, these findings suggest that food deprivation impacts liver Igf1 responsiveness to Gh via multiple mechanisms that include a downregulation of hepatic Gh receptors, modulation of the intracellular Jak2/Stat5 transduction pathway, and possible shifts in Socs-inhibitory control of igf1 gene transcription, while also demonstrating that these changes occur in concert with shifts in liver Igfbp expression and muscle Gh/Igf1 signaling pathway components.
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Affiliation(s)
- Theresa V Bersin
- Biological Sciences Department, Center for Coastal Marine Sciences, California Polytechnic State University, San Luis Obispo, CA 93407, USA
| | - Kasey L Cordova
- Biological Sciences Department, Center for Coastal Marine Sciences, California Polytechnic State University, San Luis Obispo, CA 93407, USA
| | - Meredith L Journey
- Lynker Technology, 202 Church St SE #536, Leesburg, VA 20175, USA; Under Contract to Environmental and Fisheries Sciences Division, Northwest Fisheries Science Center, National Marine Fisheries Service, National Oceanic and Atmospheric Administration, Seattle, WA 98112, USA
| | - Brian R Beckman
- Environmental and Fisheries Sciences Division, Northwest Fisheries Science Center, National Marine Fisheries Service, National Oceanic and Atmospheric Administration, Seattle, WA 98112, USA
| | - Sean C Lema
- Biological Sciences Department, Center for Coastal Marine Sciences, California Polytechnic State University, San Luis Obispo, CA 93407, USA.
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Schwarzer M, Gautam UK, Makki K, Lambert A, Brabec T, Joly A, Šrůtková D, Poinsot P, Novotná T, Geoffroy S, Courtin P, Hermanová PP, Matos RC, Landry JJM, Gérard C, Bulteau AL, Hudcovic T, Kozáková H, Filipp D, Chapot-Chartier MP, Šinkora M, Peretti N, Boneca IG, Chamaillard M, Vidal H, De Vadder F, Leulier F. Microbe-mediated intestinal NOD2 stimulation improves linear growth of undernourished infant mice. Science 2023; 379:826-833. [PMID: 36821686 DOI: 10.1126/science.ade9767] [Citation(s) in RCA: 50] [Impact Index Per Article: 25.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2022] [Accepted: 01/04/2023] [Indexed: 02/25/2023]
Abstract
The intestinal microbiota is known to influence postnatal growth. We previously found that a strain of Lactiplantibacillus plantarum (strain LpWJL) buffers the adverse effects of chronic undernutrition on the growth of juvenile germ-free mice. Here, we report that LpWJL sustains the postnatal growth of malnourished conventional animals and supports both insulin-like growth factor-1 (IGF-1) and insulin production and activity. We have identified cell walls isolated from LpWJL, as well as muramyl dipeptide and mifamurtide, as sufficient cues to stimulate animal growth despite undernutrition. Further, we found that NOD2 is necessary in intestinal epithelial cells for LpWJL-mediated IGF-1 production and for postnatal growth promotion in malnourished conventional animals. These findings indicate that, coupled with renutrition, bacteria cell walls or purified NOD2 ligands have the potential to alleviate stunting.
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Affiliation(s)
- Martin Schwarzer
- Laboratory of Gnotobiology, Institute of Microbiology of the Czech Academy of Sciences, 54922 Novy Hradek, Czech Republic
- Institut de Génomique Fonctionnelle de Lyon, Ecole Normale Supérieure de Lyon, CNRS UMR5242, UCBL Lyon-1, F-69007 Lyon, France
| | - Umesh Kumar Gautam
- Laboratory of Gnotobiology, Institute of Microbiology of the Czech Academy of Sciences, 54922 Novy Hradek, Czech Republic
| | - Kassem Makki
- Institut de Génomique Fonctionnelle de Lyon, Ecole Normale Supérieure de Lyon, CNRS UMR5242, UCBL Lyon-1, F-69007 Lyon, France
- CarMeN Laboratory, INSERM, INRAE, Université Claude Bernard Lyon 1, 69310 Pierre-Bénite, France
| | - Anne Lambert
- Institut de Génomique Fonctionnelle de Lyon, Ecole Normale Supérieure de Lyon, CNRS UMR5242, UCBL Lyon-1, F-69007 Lyon, France
| | - Tomáš Brabec
- Laboratory of Immunobiology, Institute of Molecular Genetics of the Czech Academy of Sciences, 14220 Prague, Czech Republic
| | - Amélie Joly
- Institut de Génomique Fonctionnelle de Lyon, Ecole Normale Supérieure de Lyon, CNRS UMR5242, UCBL Lyon-1, F-69007 Lyon, France
| | - Dagmar Šrůtková
- Laboratory of Gnotobiology, Institute of Microbiology of the Czech Academy of Sciences, 54922 Novy Hradek, Czech Republic
| | - Pierre Poinsot
- Institut de Génomique Fonctionnelle de Lyon, Ecole Normale Supérieure de Lyon, CNRS UMR5242, UCBL Lyon-1, F-69007 Lyon, France
- CarMeN Laboratory, INSERM, INRAE, Université Claude Bernard Lyon 1, 69310 Pierre-Bénite, France
- Univ Lyon, Hospices Civil de Lyon, Gastro-enterology and Pediatric Nutrition, Hôpital Femme Mere Enfant, F-69500 Bron, France
| | - Tereza Novotná
- Laboratory of Gnotobiology, Institute of Microbiology of the Czech Academy of Sciences, 54922 Novy Hradek, Czech Republic
| | - Stéphanie Geoffroy
- Institut de Génomique Fonctionnelle de Lyon, Ecole Normale Supérieure de Lyon, CNRS UMR5242, UCBL Lyon-1, F-69007 Lyon, France
| | - Pascal Courtin
- Université Paris-Saclay, INRAE, AgroParisTech, Micalis Institute, 78350 Jouy-en-Josas, France
| | - Petra Petr Hermanová
- Laboratory of Gnotobiology, Institute of Microbiology of the Czech Academy of Sciences, 54922 Novy Hradek, Czech Republic
| | - Renata C Matos
- Institut de Génomique Fonctionnelle de Lyon, Ecole Normale Supérieure de Lyon, CNRS UMR5242, UCBL Lyon-1, F-69007 Lyon, France
| | - Jonathan J M Landry
- Genomics Core Facility, European Molecular Biology Laboratory, 69117 Heidelberg, Germany
| | - Céline Gérard
- CarMeN Laboratory, INSERM, INRAE, Université Claude Bernard Lyon 1, 69310 Pierre-Bénite, France
| | - Anne-Laure Bulteau
- Institut de Génomique Fonctionnelle de Lyon, Ecole Normale Supérieure de Lyon, CNRS UMR5242, UCBL Lyon-1, F-69007 Lyon, France
| | - Tomáš Hudcovic
- Laboratory of Gnotobiology, Institute of Microbiology of the Czech Academy of Sciences, 54922 Novy Hradek, Czech Republic
| | - Hana Kozáková
- Laboratory of Gnotobiology, Institute of Microbiology of the Czech Academy of Sciences, 54922 Novy Hradek, Czech Republic
| | - Dominik Filipp
- Laboratory of Immunobiology, Institute of Molecular Genetics of the Czech Academy of Sciences, 14220 Prague, Czech Republic
| | | | - Marek Šinkora
- Laboratory of Gnotobiology, Institute of Microbiology of the Czech Academy of Sciences, 54922 Novy Hradek, Czech Republic
| | - Noël Peretti
- CarMeN Laboratory, INSERM, INRAE, Université Claude Bernard Lyon 1, 69310 Pierre-Bénite, France
- Univ Lyon, Hospices Civil de Lyon, Gastro-enterology and Pediatric Nutrition, Hôpital Femme Mere Enfant, F-69500 Bron, France
| | - Ivo Gomperts Boneca
- Institut Pasteur, Université Paris Cité, CNRS UMR6047, INSERM U1306, Biology and Genetics of the Bacterial Cell Wall Unit, F-75015 Paris, France
| | | | - Hubert Vidal
- CarMeN Laboratory, INSERM, INRAE, Université Claude Bernard Lyon 1, 69310 Pierre-Bénite, France
| | - Filipe De Vadder
- Institut de Génomique Fonctionnelle de Lyon, Ecole Normale Supérieure de Lyon, CNRS UMR5242, UCBL Lyon-1, F-69007 Lyon, France
| | - François Leulier
- Institut de Génomique Fonctionnelle de Lyon, Ecole Normale Supérieure de Lyon, CNRS UMR5242, UCBL Lyon-1, F-69007 Lyon, France
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Celino-Brady FT, Breves JP, Seale AP. Sex-specific responses to growth hormone and luteinizing hormone in a model teleost, the Mozambique tilapia. Gen Comp Endocrinol 2022; 329:114119. [PMID: 36029822 DOI: 10.1016/j.ygcen.2022.114119] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/09/2022] [Revised: 08/21/2022] [Accepted: 08/22/2022] [Indexed: 11/20/2022]
Abstract
Across the vertebrate lineage, sexual dimorphism in body size is a common phenomenon that results from trade-offs between growth and reproduction. To address how key hormones that regulate growth and reproduction interact in teleost fishes, we studied Mozambique tilapia (Oreochromis mossambicus) to determine whether the activities of luteinizing hormone (Lh) are modulated by growth hormone (Gh), and conversely, whether targets of Gh are affected by the presence of Lh. In particular, we examined how gonadal morphology and specific gene transcripts responded to ovine GH (oGH) and/or LH (oLH) in hypophysectomized male and female tilapia. Hypophysectomized females exhibited a diminished gonadosomatic index (GSI) concomitant with ovarian follicular atresia. The combination of oGH and oLH restored GSI and ovarian morphology to conditions observed in sham-operated controls. A similar pattern was observed for GSI in males. In control fish, gonadal gh receptor (ghr2) and estrogen receptor β (erβ) expression was higher in females versus males. A combination of oGH and oLH restored erβ and arβ in females. In males, testicular insulin-like growth factor 3 (igf3) expression was reduced following hypophysectomy and subsequently restored to control levels by either oGH or oLH. By contrast, the combination of both hormones was required to recover ovarian igf3 expression in females. In muscle, ghr2 expression was more responsive to oGH in males versus females. In the liver of hypophysectomized males, igf2 expression was diminished by both oGH and oLH; there was no effect of hypophysectomy, oGH, or oLH on igf2 expression in females. Collectively, our results indicate that gene transcripts associated with growth and reproduction exhibit sex-specific responses to oGH and oLH. These responses reflect, at least in part, how hormones mediate trade-offs between growth and reproduction, and thus sexual dimorphism, in teleost fishes.
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Affiliation(s)
- Fritzie T Celino-Brady
- Department of Human Nutrition, Food and Animal Sciences, University of Hawai'i at Mānoa, 1955 East-West Road, Honolulu, HI 96822, USA
| | - Jason P Breves
- Department of Biology, Skidmore College, 815 N. Broadway, Saratoga Springs, NY 12866, USA
| | - Andre P Seale
- Department of Human Nutrition, Food and Animal Sciences, University of Hawai'i at Mānoa, 1955 East-West Road, Honolulu, HI 96822, USA.
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Pérez-Matute P, López IP, Íñiguez M, Recio-Fernández E, Torrens R, Piñeiro-Hermida S, Alfaro-Arnedo E, Chau L, Walz C, Hoeflich A, Oteo JA, Pichel JG. IGF1R is a mediator of sex-specific metabolism in mice: Effects of age and high-fat diet. Front Endocrinol (Lausanne) 2022; 13:1033208. [PMID: 36353242 PMCID: PMC9638844 DOI: 10.3389/fendo.2022.1033208] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/31/2022] [Accepted: 09/29/2022] [Indexed: 11/13/2022] Open
Abstract
OBJECTIVE We aimed to investigate the short and long-term metabolic consequences of IGF1R systemic gene deficiency in mice. METHODS UBC-CreERT2, Igf1rfl/fl mutant mice were used to suppress IGF1R signaling in adult tissues by inducing postnatal generalized Igf1r deletion with tamoxifen. Animals were analyzed at two different ages: i) 13-weeks old young mice, and ii) 12-months old middle-aged mice. In addition, the effects of 10 weeks-long high-fat diet (HFD) were investigated in middle-aged mice. RESULTS Young IGF1R-deficient mice were insulin-resistant, with high IGF1, growth hormone (GH) and IGFBP3, as well as low IGFBP2 circulating levels. Males also presented increased triglycerides in liver. In contrast, middle-aged mice did not clearly show all of these alterations, suggesting possible compensatory effects. Middle-aged IGF1R-deficient male mice were able to counteract the negative effects induced by aging and HFD in adiposity, inflammation and glucose metabolism. A metabolic sexual dimorphism dependent on IGF1R was observed, especially in middle-aged mice. CONCLUSIONS These results demonstrate that IGF1R is involved in metabolic homeostasis, with effects modulated by diet-induced obesity and aging in a sex dependent manner. Thus, IGF1R deficiency in mice is proposed as a useful tool to understand metabolic alterations observed in patients with IGF1R gene deletions.
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Affiliation(s)
- Patricia Pérez-Matute
- Infectious Diseases, Microbiota and Metabolism Unit, Infectious Diseases Department, Center for Biomedical Research of La Rioja (CIBIR) -Hospital Universitario San Pedro, Logroño, Spain
- *Correspondence: Patricia Pérez-Matute,
| | - Icíar P. López
- Lung Cancer and Respiratory Diseases Unit. Fundación Rioja Salud, Center for Biomedical Research of La Rioja (CIBIR), Logroño, Spain
| | - María Íñiguez
- Infectious Diseases, Microbiota and Metabolism Unit, Infectious Diseases Department, Center for Biomedical Research of La Rioja (CIBIR) -Hospital Universitario San Pedro, Logroño, Spain
| | - Emma Recio-Fernández
- Infectious Diseases, Microbiota and Metabolism Unit, Infectious Diseases Department, Center for Biomedical Research of La Rioja (CIBIR) -Hospital Universitario San Pedro, Logroño, Spain
| | - Raquel Torrens
- Lung Cancer and Respiratory Diseases Unit. Fundación Rioja Salud, Center for Biomedical Research of La Rioja (CIBIR), Logroño, Spain
| | - Sergio Piñeiro-Hermida
- Miguel Servet Foundation-Navarra's Health Research Institute (IDISNA), Navarrabiomed Biomedical Research Center, Oncoimmunology Group, Pamplona, Spain
| | - Elvira Alfaro-Arnedo
- Lung Cancer and Respiratory Diseases Unit. Fundación Rioja Salud, Center for Biomedical Research of La Rioja (CIBIR), Logroño, Spain
| | - Luong Chau
- Institute for Genome Biology, Research Institute for Farm Animal Biology (FBN), Dummerstorf, Germany
| | - Christina Walz
- Institute for Genome Biology, Research Institute for Farm Animal Biology (FBN), Dummerstorf, Germany
| | - Andreas Hoeflich
- Institute for Genome Biology, Research Institute for Farm Animal Biology (FBN), Dummerstorf, Germany
| | - José A. Oteo
- Infectious Diseases, Microbiota and Metabolism Unit, Infectious Diseases Department, Center for Biomedical Research of La Rioja (CIBIR) -Hospital Universitario San Pedro, Logroño, Spain
| | - José G. Pichel
- Lung Cancer and Respiratory Diseases Unit. Fundación Rioja Salud, Center for Biomedical Research of La Rioja (CIBIR), Logroño, Spain
- Biomedical Research Networking Center on Respiratory Diseases (CIBERES), Instituto de Salud Carlos III (ISCIII), Madrid, Spain
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7
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García-Mato Á, Cervantes B, Murillo-Cuesta S, Rodríguez-de la Rosa L, Varela-Nieto I. Insulin-like Growth Factor 1 Signaling in Mammalian Hearing. Genes (Basel) 2021; 12:genes12101553. [PMID: 34680948 PMCID: PMC8535591 DOI: 10.3390/genes12101553] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2021] [Revised: 09/24/2021] [Accepted: 09/27/2021] [Indexed: 02/06/2023] Open
Abstract
Insulin-like growth factor 1 (IGF-1) is a peptide hormone belonging to the insulin family of proteins. Almost all of the biological effects of IGF-1 are mediated through binding to its high-affinity tyrosine kinase receptor (IGF1R), a transmembrane receptor belonging to the insulin receptor family. Factors, receptors and IGF-binding proteins form the IGF system, which has multiple roles in mammalian development, adult tissue homeostasis, and aging. Consequently, mutations in genes of the IGF system, including downstream intracellular targets, underlie multiple common pathologies and are associated with multiple rare human diseases. Here we review the contribution of the IGF system to our understanding of the molecular and genetic basis of human hearing loss by describing, (i) the expression patterns of the IGF system in the mammalian inner ear; (ii) downstream signaling of IGF-1 in the hearing organ; (iii) mouse mutations in the IGF system, including upstream regulators and downstream targets of IGF-1 that inform cochlear pathophysiology; and (iv) human mutations in these genes causing hearing loss.
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Affiliation(s)
- Ángela García-Mato
- Institute for Biomedical Research “Alberto Sols” (IIBm), Spanish National Research Council-Autonomous University of Madrid (CSIC-UAM), 28029 Madrid, Spain; (Á.G.-M.); (B.C.); (S.M.-C.)
- Rare Diseases Networking Biomedical Research Centre (CIBERER), CIBER, Carlos III Institute of Health, 28029 Madrid, Spain
| | - Blanca Cervantes
- Institute for Biomedical Research “Alberto Sols” (IIBm), Spanish National Research Council-Autonomous University of Madrid (CSIC-UAM), 28029 Madrid, Spain; (Á.G.-M.); (B.C.); (S.M.-C.)
- Rare Diseases Networking Biomedical Research Centre (CIBERER), CIBER, Carlos III Institute of Health, 28029 Madrid, Spain
| | - Silvia Murillo-Cuesta
- Institute for Biomedical Research “Alberto Sols” (IIBm), Spanish National Research Council-Autonomous University of Madrid (CSIC-UAM), 28029 Madrid, Spain; (Á.G.-M.); (B.C.); (S.M.-C.)
- Rare Diseases Networking Biomedical Research Centre (CIBERER), CIBER, Carlos III Institute of Health, 28029 Madrid, Spain
- La Paz Hospital Institute for Health Research (IdiPAZ), 28046 Madrid, Spain
| | - Lourdes Rodríguez-de la Rosa
- Rare Diseases Networking Biomedical Research Centre (CIBERER), CIBER, Carlos III Institute of Health, 28029 Madrid, Spain
- La Paz Hospital Institute for Health Research (IdiPAZ), 28046 Madrid, Spain
- Correspondence: (L.R.-d.l.R.); (I.V.-N.)
| | - Isabel Varela-Nieto
- Institute for Biomedical Research “Alberto Sols” (IIBm), Spanish National Research Council-Autonomous University of Madrid (CSIC-UAM), 28029 Madrid, Spain; (Á.G.-M.); (B.C.); (S.M.-C.)
- Rare Diseases Networking Biomedical Research Centre (CIBERER), CIBER, Carlos III Institute of Health, 28029 Madrid, Spain
- La Paz Hospital Institute for Health Research (IdiPAZ), 28046 Madrid, Spain
- Correspondence: (L.R.-d.l.R.); (I.V.-N.)
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8
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Lamadé EK, Hendlmeier F, Wudy SA, Blum WF, Witt SH, Rietschel M, Coenen M, Gilles M, Deuschle M. Childhood trauma and insulin-like growth factors in amniotic fluid: An exploratory analysis of 79 women. Psychoneuroendocrinology 2021; 127:105180. [PMID: 33690109 DOI: 10.1016/j.psyneuen.2021.105180] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/08/2020] [Revised: 02/26/2021] [Accepted: 02/26/2021] [Indexed: 12/15/2022]
Abstract
BACKGROUND Perinatal stress has adverse effects on fetal outcome, yet the effect of early maternal trauma on fetal outcome has scarcely been studied. We investigated effects of maternal childhood trauma and current environment on important regulators of prenatal growth, fetal insulin-like growth factor (IGF)-1 and IGF-2 in amniotic fluid and assessed the impact of IGFs on newborn anthropometrics. METHODS 79 pregnant women in their second trimester who underwent amniocentesis (15.9 ± 0.9 weeks of gestational age) and their newborns at birth were analyzed. Maternal childhood trauma was assessed using the childhood trauma questionnaire (CTQ) and current environment was operationalized by assessing maternal psychosocial, physical health and endocrine measurements in amniotic fluid. RESULTS In this exploratory analysis of 79 pregnant women, maternal childhood trauma, defined as reporting at least low scores on any of the CTQ subscales, negatively correlated with fetal IGF-1 (Mln = 3.48 vs. 2.98; p = 0.012) and IGF-2 (Mdnln = 4.99 vs. 4.70; p = 0.002). Trauma severity, defined as the overall trauma score, negatively correlated with fetal IGF-2 (r = -0.24; p = 0.037). From trauma subscales, maternal sexual abuse correlated with fetal IGF-1 (r = -0.32; p = 0.006) and IGF-2 (r = -0.39; p = 0.001). Maternal BMI negatively correlated with fetal IGF-1 (r = -0.26; p = 0.023) and IGF-2 (r = -0.29; p = 0.011). Newborn anthropometrics were operationalized by length, weight, sex, gestational age, length/gestational age and weight/gestational age at birth. Fetal weight at birth associated with a trend with fetal IGF-1 when controlling for BMI. Maternal hypothalamus-pituitary-adrenal axis activity and maternal exercise did not contribute significantly to predicting fetal IGFs. Maternal childhood trauma (β = -0.27; p = 0.011) and BMI (β = -0.24; p = 0.026) remained significantly associated with fetal IGF-1. Maternal childhood trauma (β = -0.32; p = 0.003), maternal BMI (β = -0.30; p = 0.005) and maternal sexual abuse (β = -0.22; p = 0.049) remained significantly associated with fetal IGF-2 and with a trend with fetal IGF-1 (β = -0.21; p = 0.076) when excluding women with gestational diabetes. CONCLUSION Maternal childhood trauma and BMI associate negatively with fetal IGF-1 and IGF-2 in amniotic fluid. Controlling for maternal BMI, fetal weight at birth remains associated with a trend with fetal IGF-1. The presented data suggests that childhood trauma can affect endocrine measurements of the developing next generation, providing a mechanism by which adverse maternal life events are transmitted to the next generation.
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Affiliation(s)
- Eva Kathrin Lamadé
- Department of Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany.
| | - Ferdinand Hendlmeier
- Department of Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany
| | - Stefan A Wudy
- Laboratory for Translational Hormone Analytics, Division of Pediatric Endocrinology and Diabetology, Center of Child and Adolescent Medicine, Justus Liebig University, Giessen, Germany
| | - Werner F Blum
- Laboratory for Translational Hormone Analytics, Division of Pediatric Endocrinology and Diabetology, Center of Child and Adolescent Medicine, Justus Liebig University, Giessen, Germany
| | - Stephanie H Witt
- Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany
| | - Marcella Rietschel
- Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany
| | - Michaela Coenen
- Institute for Medical Information Processing, Biometry and Epidemiology, Chair of Public Health and Health Services Research, LMU Munich, Munich, Germany; Pettenkofer School of Public Health, Munich, Germany
| | - Maria Gilles
- Department of Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany
| | - Michael Deuschle
- Department of Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany
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9
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Omolaoye TS, Windvogel SL, Du Plessis SS. The Effect of Rooibos ( Aspalathus linearis), Honeybush ( Cyclopia intermedia) and Sutherlandia ( Lessertia frutescens) on Testicular Insulin Signalling in Streptozotocin-Induced Diabetes in Wistar Rats. Diabetes Metab Syndr Obes 2021; 14:1267-1280. [PMID: 33776463 PMCID: PMC7989961 DOI: 10.2147/dmso.s285025] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/05/2020] [Accepted: 02/10/2021] [Indexed: 01/04/2023] Open
Abstract
BACKGROUND Testicular insulin signalling is altered in diabetic (DM) males. While unravelling the mechanism through which DM exert these detrimental effects, studies have shown the importance of insulin regulation in glucose homeostasis, and how a lack in insulin secretion indirectly led to reduced male fertility. The current study aimed to investigate the role of rooibos, honeybush and Sutherlandia on insulin signalling in the testicular tissue of type I diabetic rats. METHODS Animals (n=60) were randomly divided into six groups. The groups include a control group, a vehicle group, and diabetes was induced in the remainder of animals via a single intraperitoneal injection of STZ at 45mg/kg. The remaining four groups included a diabetic control (DC), diabetic + rooibos (DRF), diabetic + honeybush (DHB) and diabetic + Sutherlandia group (DSL). Animals were sacrificed after seven weeks of treatment, and blood and testes were collected. RESULTS All diabetic groups (DC, DRF, DHB, DSL) presented with a significant increase in blood glucose levels after diabetes induction compared to the control and vehicle (p<0.001). The DC animals presented with decreased testicular protein expression of IRS-1, PkB/Akt and GLUT4 compared to controls. DRF and DHB animals displayed an acute upregulation in IRS-1, while the DSL group showed improvement in IRS-2 compared to DC. Although, DRF animals presented with a decrease in PkB/Akt, DHB and DSL animals displayed upregulation (22.3%, 48%) compared to controls, respectively. CONCLUSION The results taken together, it can be suggested that these infusions may enhance insulin signalling through diverse pathways.
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Affiliation(s)
- Temidayo S Omolaoye
- Division of Medical Physiology, Faculty of Medicine and Health Sciences, Stellenbosch University, Tygerberg, South Africa
- Department of Basic Sciences, College of Medicine, Mohammed Bin Rashid University of Medicine and Health Sciences, Dubai, United Arab Emirates
| | - Shantal Lynn Windvogel
- Division of Medical Physiology, Faculty of Medicine and Health Sciences, Stellenbosch University, Tygerberg, South Africa
- Centre for Cardio-Metabolic Research in Africa, Stellenbosch University, Cape Town, South Africa
| | - Stefan S Du Plessis
- Division of Medical Physiology, Faculty of Medicine and Health Sciences, Stellenbosch University, Tygerberg, South Africa
- Department of Basic Sciences, College of Medicine, Mohammed Bin Rashid University of Medicine and Health Sciences, Dubai, United Arab Emirates
- Correspondence: Stefan S Du Plessis Department of Basic Sciences, College of Medicine, Mohammed Bin Rashid University of Medicine and Health Sciences, P.O. Box 505055, Dubai, 505055, United Arab Emirates Email
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10
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López-Márquez A, Carrasco-López C, Fernández-Méndez C, Santisteban P. Unraveling the Complex Interplay Between Transcription Factors and Signaling Molecules in Thyroid Differentiation and Function, From Embryos to Adults. Front Endocrinol (Lausanne) 2021; 12:654569. [PMID: 33959098 PMCID: PMC8095082 DOI: 10.3389/fendo.2021.654569] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/16/2021] [Accepted: 03/29/2021] [Indexed: 12/29/2022] Open
Abstract
Thyroid differentiation of progenitor cells occurs during embryonic development and in the adult thyroid gland, and the molecular bases of these complex and finely regulated processes are becoming ever more clear. In this Review, we describe the most recent advances in the study of transcription factors, signaling molecules and regulatory pathways controlling thyroid differentiation and development in the mammalian embryo. We also discuss the maintenance of the adult differentiated phenotype to ensure the biosynthesis of thyroid hormones. We will focus on endoderm-derived thyroid epithelial cells, which are responsible for the formation of the thyroid follicle, the functional unit of the thyroid gland. The use of animal models and pluripotent stem cells has greatly aided in providing clues to the complicated puzzle of thyroid development and function in adults. The so-called thyroid transcription factors - Nkx2-1, Foxe1, Pax8 and Hhex - were the first pieces of the puzzle identified in mice. Other transcription factors, either acting upstream of or directly with the thyroid transcription factors, were subsequently identified to, almost, complete the puzzle. Among them, the transcription factors Glis3, Sox9 and the cofactor of the Hippo pathway Taz, have emerged as important players in thyroid differentiation and development. The involvement of signaling molecules increases the complexity of the puzzle. In this context, the importance of Bmps, Fgfs and Shh signaling at the onset of development, and of TSH, IGF1 and TGFβ both at the end of terminal differentiation in embryos and in the adult thyroid, are well recognized. All of these aspects are covered herein. Thus, readers will be able to visualize the puzzle of thyroid differentiation with most - if not all - of the pieces in place.
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Affiliation(s)
- Arístides López-Márquez
- Instituto de Investigaciones Biomédicas “Alberto Sols”, Consejo Superior de Investigaciones Científicas (CSIC) y Universidad Autónoma de Madrid (UAM), Madrid, Spain
- Laboratorio de Investigación Aplicada en Enfermedades Neuromusculares, Unidad de Patología Neuromuscular, Servicio de Neuropediatría, Institut de Recerca Sant Joan de Déu, Esplugues de Llobregat, Spain
| | - Carlos Carrasco-López
- Instituto de Investigaciones Biomédicas “Alberto Sols”, Consejo Superior de Investigaciones Científicas (CSIC) y Universidad Autónoma de Madrid (UAM), Madrid, Spain
- Centro de Investigación Biomédica en Red (CIBERONC), Instituto de Salud Carlos III, Madrid, Spain
| | - Celia Fernández-Méndez
- Instituto de Investigaciones Biomédicas “Alberto Sols”, Consejo Superior de Investigaciones Científicas (CSIC) y Universidad Autónoma de Madrid (UAM), Madrid, Spain
| | - Pilar Santisteban
- Instituto de Investigaciones Biomédicas “Alberto Sols”, Consejo Superior de Investigaciones Científicas (CSIC) y Universidad Autónoma de Madrid (UAM), Madrid, Spain
- Centro de Investigación Biomédica en Red (CIBERONC), Instituto de Salud Carlos III, Madrid, Spain
- *Correspondence: Pilar Santisteban,
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11
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Breves JP, Springer-Miller RH, Chenoweth DA, Paskavitz AL, Chang AYH, Regish AM, Einarsdottir IE, Björnsson BT, McCormick SD. Cortisol regulates insulin-like growth-factor binding protein (igfbp) gene expression in Atlantic salmon parr. Mol Cell Endocrinol 2020; 518:110989. [PMID: 32835784 DOI: 10.1016/j.mce.2020.110989] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/07/2020] [Revised: 08/10/2020] [Accepted: 08/11/2020] [Indexed: 02/08/2023]
Abstract
The growth hormone (Gh)/insulin-like growth-factor (Igf)/Igf binding protein (Igfbp) system regulates growth and osmoregulation in salmonid fishes, but how this system interacts with other endocrine systems is largely unknown. Given the well-documented consequences of mounting a glucocorticoid stress response on growth, we hypothesized that cortisol inhibits anabolic processes by modulating the expression of hepatic igfbp mRNAs. Atlantic salmon (Salmo salar) parr were implanted intraperitoneally with cortisol implants (0, 10, and 40 μg g-1 body weight) and sampled after 3 or 14 days. Cortisol elicited a dose-dependent reduction in specific growth rate (SGR) after 14 days. While plasma Gh and Igf1 levels were unchanged, hepatic igf1 mRNA was diminished and hepatic igfbp1b1 and -1b2 were stimulated by the high cortisol dose. Plasma Igf1 was positively correlated with SGR at 14 days. Hepatic gh receptor (ghr), igfbp1a, -2a, -2b1, and -2b2 levels were not impacted by cortisol. Muscle igf2, but not igf1 or ghr, levels were stimulated at 3 days by the high cortisol dose. As both cortisol and the Gh/Igf axis promote seawater (SW) tolerance, and particular igfbps respond to SW exposure, we also assessed whether cortisol coordinates the expression of branchial igfbps and genes associated with ion transport. Cortisol stimulated branchial igfbp5b2 levels in parallel with Na+/K+-ATPase (NKA) activity and nka-α1b, Na+/K+/2Cl--cotransporter 1 (nkcc1), and cystic fibrosis transmembrane regulator 1 (cftr1) mRNA levels. The collective results indicate that cortisol modulates the growth of juvenile salmon via the regulation of hepatic igfbp1s whereas no clear links between cortisol and branchial igfbps previously shown to be salinity-responsive could be established.
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Affiliation(s)
- J P Breves
- Department of Biology, Skidmore College, 815 N. Broadway, Saratoga Springs, NY, 12866, USA.
| | - R H Springer-Miller
- Department of Biology, Skidmore College, 815 N. Broadway, Saratoga Springs, NY, 12866, USA
| | - D A Chenoweth
- Department of Biology, Skidmore College, 815 N. Broadway, Saratoga Springs, NY, 12866, USA
| | - A L Paskavitz
- Department of Biology, Skidmore College, 815 N. Broadway, Saratoga Springs, NY, 12866, USA
| | - A Y H Chang
- Department of Biology, Skidmore College, 815 N. Broadway, Saratoga Springs, NY, 12866, USA
| | - A M Regish
- U.S. Geological Survey, Leetown Science Center, Conte Anadromous Fish Research Laboratory, One Migratory Way, Turners Falls, MA, 01376, USA
| | - I E Einarsdottir
- Fish Endocrinology Laboratory, Department of Biological and Environmental Sciences, University of Gothenburg, Box 463 SE, 40530, Göteborg, Sweden
| | - B Th Björnsson
- Fish Endocrinology Laboratory, Department of Biological and Environmental Sciences, University of Gothenburg, Box 463 SE, 40530, Göteborg, Sweden
| | - S D McCormick
- U.S. Geological Survey, Leetown Science Center, Conte Anadromous Fish Research Laboratory, One Migratory Way, Turners Falls, MA, 01376, USA
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12
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Chen Y, Zhou Y, Yang X, Cao Z, Chen X, Qin Q, Liu C, Sun Y. Insulin-like growth factor binding protein 3 gene of golden pompano (TroIGFBP3) promotes antimicrobial immune defense. FISH & SHELLFISH IMMUNOLOGY 2020; 103:47-57. [PMID: 32278114 DOI: 10.1016/j.fsi.2020.04.002] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/19/2020] [Revised: 03/31/2020] [Accepted: 04/02/2020] [Indexed: 06/11/2023]
Abstract
Insulin-like growth factor binding protein 3 (IGFBP3), an important member of the IGFBP family, plays an important biological role in regulating cellular proliferation, differentiation, growth, apoptosis, and innate immunity. However, studies concerning IGFBP3 in teleosts are very limited and IGFBP3 function remains unclear. In this study, we conducted both in vivo and in vitro functional analyses of an IGFBP3 (TroIGFBP3) from the teleost fish golden pompano (Trachinotus ovatus). TroIGFBP3 is composed of 286 amino acid residues and shares a high amino acid sequence similarity (50.18%-93.71%) with other IGFBP3 sequences in humans and teleosts. TroIGFBP3 was widely distributed in various tissues, with the highest expression in the liver. TroIGFBP3 expression was significantly upregulated following Vibrio harveyi infection. The results of in vitro assays showed that TroIGFBP3 could stimulate macrophage activation and promote peripheral blood leukocytes (PBLs) proliferation. Meanwhile, TroIGFBP3 overexpression significantly inhibited bacterial infection in fish tissues, whereas TroIGFBP3 knockdown resulted in increased bacterial dissemination and colonization in golden pompano tissues in vivo. Furthermore, recombinant TroIGFBP3 could inhibit cellular proliferation and promote apoptosis of mouse tumor cells. Taken together, these results indicated that TroIGFBP3 plays a significant role in innate antibacterial immunity and provides a theoretical foundation for investigating the function of IGFBP3 in fish immune response.
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Affiliation(s)
- Yang Chen
- State Key Laboratory of Marine Resource Utilization in South China Sea, Hainan University, Haikou, Hainan, 570228, PR China; Key Laboratory of Tropical Hydrobiology and Biotechnology of Hainan Province, Haikou, Hainan, 570228, PR China
| | - Yongcan Zhou
- State Key Laboratory of Marine Resource Utilization in South China Sea, Hainan University, Haikou, Hainan, 570228, PR China; Key Laboratory of Tropical Hydrobiology and Biotechnology of Hainan Province, Haikou, Hainan, 570228, PR China
| | - Xiaoyu Yang
- State Key Laboratory of Marine Resource Utilization in South China Sea, Hainan University, Haikou, Hainan, 570228, PR China; College of Marine Sciences, South China Agricultural University, Guangzhou, Guangdong, 510642, PR China
| | - Zhenjie Cao
- State Key Laboratory of Marine Resource Utilization in South China Sea, Hainan University, Haikou, Hainan, 570228, PR China; Key Laboratory of Tropical Hydrobiology and Biotechnology of Hainan Province, Haikou, Hainan, 570228, PR China
| | - Xiaojuan Chen
- Key Laboratory of Tropical Hydrobiology and Biotechnology of Hainan Province, Haikou, Hainan, 570228, PR China
| | - Qiwei Qin
- College of Marine Sciences, South China Agricultural University, Guangzhou, Guangdong, 510642, PR China
| | - Chunsheng Liu
- Key Laboratory of Tropical Hydrobiology and Biotechnology of Hainan Province, Haikou, Hainan, 570228, PR China
| | - Yun Sun
- State Key Laboratory of Marine Resource Utilization in South China Sea, Hainan University, Haikou, Hainan, 570228, PR China; Key Laboratory of Tropical Hydrobiology and Biotechnology of Hainan Province, Haikou, Hainan, 570228, PR China.
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13
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Zeng Z, Meyer KF, Lkhagvadorj K, Kooistra W, Reinders-Luinge M, Xu X, Huo X, Song J, Plösch T, Hylkema MN. Prenatal smoke effect on mouse offspring Igf1 promoter methylation from fetal stage to adulthood is organ and sex specific. Am J Physiol Lung Cell Mol Physiol 2020; 318:L549-L561. [PMID: 31913647 DOI: 10.1152/ajplung.00293.2019] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Prenatal smoke exposure (PSE) is associated with reduced birth weight, impaired fetal development, and increased risk for diseases later in life. Changes in DNA methylation may be involved, as multiple large-scale epigenome-wide association studies showed that PSE is robustly associated with DNA methylation changes in blood among offspring in early life. Insulin-like growth factor-1 (IGF1) is important in growth, differentiation, and repair processes after injury. However, no studies investigated the organ-specific persistence of PSE-induced methylation change of Igf1 into adulthood. Based on our previous studies on the PSE effect on Igf1 promoter methylation in fetal and neonatal mouse offspring, we now have extended our studies to adulthood. Our data show that basal Igf1 promoter methylation generally increased in the lung but decreased in the liver (except for 2 persistent CpG sites in both organs) across three different developmental stages. PSE changed Igf1 promoter methylation in all three developmental stages, which was organ and sex specific. The PSE effect was less pronounced in adult offspring compared with the fetal and neonatal stages. In addition, the PSE effect in the adult stage was more pronounced in the lung compared with the liver. For most CpG sites, an inverse correlation was found for promoter methylation and mRNA expression when the data of all three stages were combined. This was more prominent in the liver. Our findings provide additional evidence for sex- and organ-dependent prenatal programming, which supports the developmental origins of health and disease (DOHaD) hypothesis.
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Affiliation(s)
- Zhijun Zeng
- Department of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen, Hanzeplein, Groningen, The Netherlands
- University of Groningen, University Medical Center Groningen, GRIAC Research Institute, Hanzeplein, Groningen, The Netherlands
- Laboratory of Environmental Medicine and Developmental Toxicology, Shantou University Medical College, Shantou, China
| | - Karolin F Meyer
- Department of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen, Hanzeplein, Groningen, The Netherlands
- University of Groningen, University Medical Center Groningen, GRIAC Research Institute, Hanzeplein, Groningen, The Netherlands
| | - Khosbayar Lkhagvadorj
- Department of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen, Hanzeplein, Groningen, The Netherlands
- University of Groningen, University Medical Center Groningen, GRIAC Research Institute, Hanzeplein, Groningen, The Netherlands
| | - Wierd Kooistra
- Department of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen, Hanzeplein, Groningen, The Netherlands
| | - Marjan Reinders-Luinge
- Department of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen, Hanzeplein, Groningen, The Netherlands
| | - Xijin Xu
- Laboratory of Environmental Medicine and Developmental Toxicology, Shantou University Medical College, Shantou, China
- Department of Cell Biology and Genetics, Shantou University Medical College, Shantou, China
| | - Xia Huo
- School of Environment, Guangzhou Key Laboratory of Environmental Exposure and Health, Guangdong Key Laboratory of Environmental Pollution and Health, Jinan University, Guangzhou, China
| | - Juan Song
- Department of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen, Hanzeplein, Groningen, The Netherlands
- University of Groningen, University Medical Center Groningen, GRIAC Research Institute, Hanzeplein, Groningen, The Netherlands
| | - Torsten Plösch
- Department of Obstetrics and Gynecology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Machteld N Hylkema
- Department of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen, Hanzeplein, Groningen, The Netherlands
- University of Groningen, University Medical Center Groningen, GRIAC Research Institute, Hanzeplein, Groningen, The Netherlands
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14
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Strobel JS, Hack NL, Label KT, Cordova KL, Bersin TV, Journey ML, Beckman BR, Lema SC. Effects of food deprivation on plasma insulin-like growth factor-1 (Igf1) and Igf binding protein (Igfbp) gene transcription in juvenile cabezon (Scorpaenichthys marmoratus). Gen Comp Endocrinol 2020; 286:113319. [PMID: 31715138 DOI: 10.1016/j.ygcen.2019.113319] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/19/2019] [Revised: 10/25/2019] [Accepted: 11/08/2019] [Indexed: 12/25/2022]
Abstract
The growth hormone (GH)/insulin-like growth factor (Igf) endocrine axis regulates somatic growth in the face of changing environmental conditions. In actinopterygian fishes, food availability is a key modulator of the somatotropic axis, with lower food intake generally depressing liver Igf1 release to diminish growth. Igf1 signaling, however, also involves several distinct IGF binding proteins (Igfbps), and the functional roles of many of these Igfbps in affecting growth during shifting food availability remain uncertain. Here, we tested how complete food deprivation (fasting) affected gene transcription for paralogs of all six types of Igfbps in the liver and fast-twitch skeletal muscle of cabezon (Scorpaenichthys marmoratus), a nearshore marine fish important for recreational fisheries in the eastern North Pacific Ocean. Juvenile cabezon were maintained as either fed (6% mass food⋅g fish wet mass-1⋅d-1) or fasted for 14 d. Fasted fish exhibited a lower body condition (K), a depressed mass-specific growth rate (SGR), and reduced plasma concentrations of Igf1. In the liver, fasting reduced the relative abundance of gene transcripts encoding Igfbps igfbp2a and igfbp2b, while significantly elevating mRNA levels for igfbp1a, igfbp1b, igfbp3b, and igfbp4. Fasting also reduced hepatic mRNA levels of GH receptor-1 (ghr1) - but not GH receptor-2 (ghr2) - supporting the idea that changes in liver sensitivity to GH may underlie the decline in plasma Igf1 during food deprivation. In skeletal muscle, fasting downregulated gene transcripts encoding igf1, igfbp2b, igfbp5b, and igfbp6b, while also upregulating mRNAs for igf2 and ghr2. These data demonstrate isoform-specific regulation of Igfbps in liver and skeletal muscle in cabezon experiencing food deprivation and reinforce the idea that the repertoire of duplicated Igfbp genes that evolved in actinopterygian fishes supports a diverse scope of endocrine and paracrine functions.
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Affiliation(s)
- Jackson S Strobel
- Biological Sciences Department, Center for Coastal Marine Sciences, California Polytechnic State University, San Luis Obispo, CA 93407, USA
| | - Nicole L Hack
- Biological Sciences Department, Center for Coastal Marine Sciences, California Polytechnic State University, San Luis Obispo, CA 93407, USA
| | - Kevin T Label
- Biological Sciences Department, Center for Coastal Marine Sciences, California Polytechnic State University, San Luis Obispo, CA 93407, USA
| | - Kasey L Cordova
- Biological Sciences Department, Center for Coastal Marine Sciences, California Polytechnic State University, San Luis Obispo, CA 93407, USA
| | - Theresa V Bersin
- Biological Sciences Department, Center for Coastal Marine Sciences, California Polytechnic State University, San Luis Obispo, CA 93407, USA
| | - Meredith L Journey
- Lynker Technology, 202 Church St SE #536, Leesburg, VA 20175, Under Contract to Environmental and Fisheries Sciences Division, Northwest Fisheries Science Center, National Marine Fisheries Service, National Oceanic and Atmospheric Administration, Seattle Washington 98112, USA
| | - Brian R Beckman
- Environmental and Fisheries Sciences Division, Northwest Fisheries Science Center, National Marine Fisheries Service, National Oceanic and Atmospheric Administration, Seattle, Washington 98112, USA
| | - Sean C Lema
- Biological Sciences Department, Center for Coastal Marine Sciences, California Polytechnic State University, San Luis Obispo, CA 93407, USA.
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15
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Celino-Brady FT, Lerner DT, Seale AP. Experimental Approaches for Characterizing the Endocrine-Disrupting Effects of Environmental Chemicals in Fish. Front Endocrinol (Lausanne) 2020; 11:619361. [PMID: 33716955 PMCID: PMC7947849 DOI: 10.3389/fendo.2020.619361] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/20/2020] [Accepted: 12/30/2020] [Indexed: 12/22/2022] Open
Abstract
Increasing industrial and agricultural activities have led to a disturbing increase of pollutant discharges into the environment. Most of these pollutants can induce short-term, sustained or delayed impacts on developmental, physiological, and behavioral processes that are often regulated by the endocrine system in vertebrates, including fish, thus they are termed endocrine-disrupting chemicals (EDCs). Physiological impacts resulting from the exposure of these vertebrates to EDCs include abnormalities in growth and reproductive development, as many of the prevalent chemicals are capable of binding the receptors to sex steroid hormones. The approaches employed to investigate the action and impact of EDCs is largely dependent on the specific life history and habitat of each species, and the type of chemical that organisms are exposed to. Aquatic vertebrates, such as fish, are among the first organisms to be affected by waterborne EDCs, an attribute that has justified their wide-spread use as sentinel species. Many fish species are exposed to these chemicals in the wild, for either short or prolonged periods as larvae, adults, or both, thus, studies are typically designed to focus on either acute or chronic exposure at distinct developmental stages. The aim of this review is to provide an overview of the approaches and experimental methods commonly used to characterize the effects of some of the environmentally prevalent and emerging EDCs, including 17 α-ethinylestradiol, nonylphenol, BPA, phthalates, and arsenic; and the pervasive and potential carriers of EDCs, microplastics, on reproduction and growth. In vivo and in vitro studies are designed and employed to elucidate the direct effects of EDCs at the organismal and cellular levels, respectively. In silico approaches, on the other hand, comprise computational methods that have been more recently applied with the potential to replace extensive in vitro screening of EDCs. These approaches are discussed in light of model species, age and duration of EDC exposure.
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Affiliation(s)
- Fritzie T. Celino-Brady
- Department of Human Nutrition, Food and Animal Sciences, University of Hawai’i at Mānoa, Honolulu, HI, United States
| | - Darren T. Lerner
- University of Hawai’i Sea Grant College Program, University of Hawai’i at Mānoa, Honolulu, HI, United States
| | - Andre P. Seale
- Department of Human Nutrition, Food and Animal Sciences, University of Hawai’i at Mānoa, Honolulu, HI, United States
- *Correspondence: Andre P. Seale,
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16
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Celino-Brady FT, Petro-Sakuma CK, Breves JP, Lerner DT, Seale AP. Early-life exposure to 17β-estradiol and 4-nonylphenol impacts the growth hormone/insulin-like growth-factor system and estrogen receptors in Mozambique tilapia, Oreochromis mossambicus. AQUATIC TOXICOLOGY (AMSTERDAM, NETHERLANDS) 2019; 217:105336. [PMID: 31733503 PMCID: PMC6935514 DOI: 10.1016/j.aquatox.2019.105336] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/04/2019] [Revised: 09/28/2019] [Accepted: 10/14/2019] [Indexed: 05/31/2023]
Abstract
It is widely recognized that endocrine disrupting chemicals (EDCs) released into the environment through anthropogenic activities can have short-term impacts on physiological and behavioral processes and/or sustained or delayed long-term developmental effects on aquatic organisms. While numerous studies have characterized the effects of EDCs on temperate fishes, less is known on the effects of EDCs on the growth and reproductive physiology of tropical species. To determine the long-term effects of early-life exposure to common estrogenic chemicals, we exposed Mozambique tilapia (Oreochromis mossambicus) yolk-sac fry to 17β-estradiol (E2) and nonylphenol (NP) and subsequently characterized the expression of genes involved in growth and reproduction in adults. Fry were exposed to waterborne E2 (0.1 and 1 μg/L) and NP (10 and 100 μg/L) for 21 days. After the exposure period, juveniles were reared for an additional 112 days until males were sampled. Gonadosomatic index was elevated in fish exposed to E2 (0.1 μg/L) while hepatosomatic index was decreased by exposure to NP (100 μg/L). Exposure to E2 (0.1 μg/L) induced hepatic growth hormone receptor (ghr) mRNA expression. The high concentration of E2 (1 μg/L), and both concentrations of NP, increased hepatic insulin-like growth-factor 1 (igf1) expression; E2 and NP did not affect hepatic igf2 and pituitary growth hormone (gh) levels. Both E2 (1 μg/L) and NP (10 μg/L) induced hepatic igf binding protein 1b (igfbp1b) levels while only NP (100 μg/L) induced hepatic igfbp2b levels. By contrast, hepatic igfbp6b was reduced in fish exposed to E2 (1 μg/L). There were no effects of E2 or NP on hepatic igfbp4 and igfbp5a expression. Although the expression of three vitellogenin transcripts was not affected, E2 and NP stimulated hepatic estrogen receptor (erα and erβ) mRNA expression. We conclude that tilapia exposed to E2 and NP as yolk-sac fry exhibit subsequent changes in the endocrine systems that control growth and reproduction during later life stages.
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Affiliation(s)
- Fritzie T Celino-Brady
- Department of Human Nutrition, Food and Animal Sciences, University of Hawai'i at Mānoa, 1955 East-West Road, Honolulu, HI 96822, USA.
| | - Cody K Petro-Sakuma
- Department of Human Nutrition, Food and Animal Sciences, University of Hawai'i at Mānoa, 1955 East-West Road, Honolulu, HI 96822, USA.
| | - Jason P Breves
- Department of Biology, Skidmore College, 815 N. Broadway, Saratoga Springs, NY 12866, USA.
| | - Darren T Lerner
- University of Hawai'i Sea Grant College Program, University of Hawai'i at Mānoa, 2525 Correa Road, Honolulu, HI 96822, USA.
| | - Andre P Seale
- Department of Human Nutrition, Food and Animal Sciences, University of Hawai'i at Mānoa, 1955 East-West Road, Honolulu, HI 96822, USA.
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Kasprzak A, Adamek A. Insulin-Like Growth Factor 2 (IGF2) Signaling in Colorectal Cancer-From Basic Research to Potential Clinical Applications. Int J Mol Sci 2019; 20:ijms20194915. [PMID: 31623387 PMCID: PMC6801528 DOI: 10.3390/ijms20194915] [Citation(s) in RCA: 53] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2019] [Revised: 09/27/2019] [Accepted: 09/30/2019] [Indexed: 02/07/2023] Open
Abstract
Colorectal cancer (CRC) is one of the most common cancers in men and women worldwide as well as is the leading cause of death in the western world. Almost a third of the patients has or will develop liver metastases. While genetic as well as epigenetic mechanisms are important in CRC pathogenesis, the basis of the most cases of cancer is unknown. High spatial and inter-patient variability of the molecular alterations qualifies this cancer in the group of highly heterogeneous tumors, which makes it harder to elucidate the mechanisms underlying CRC progression. Determination of highly sensitive and specific early diagnosis markers and understanding the cellular and molecular mechanism(s) of cancer progression are still a challenge of the current era in oncology of solid tumors. One of the accepted risk factors for CRC development is overexpression of insulin-like growth factor 2 (IGF2), a 7.5-kDa peptide produced by liver and many other tissues. IGF2 is the first gene discovered to be parentally imprinted. Loss of imprinting (LOI) or aberrant imprinting of IGF2 could lead to IGF2 overexpression, increased cell proliferation, and CRC development. IGF2 as a mitogen is associated with increased risk of developing colorectal neoplasia. Higher serum IGF2 concentration as well as its tissue overexpression in CRC compared to control are associated with metastasis. IGF2 protein was one of the three candidates for a selective marker of CRC progression and staging. Recent research indicates dysregulation of different micro- and long non-coding RNAs (miRNAs and lncRNAs, respectively) embedded within the IGF2 gene in CRC carcinogenesis, with some of them indicated as potential diagnostic and prognostic CRC biomarkers. This review systematises the knowledge on the role of genetic and epigenetic instabilities of IGF2 gene, free (active form of IGF2) and IGF-binding protein (IGFBP) bound (inactive form), paracrine/autocrine secretion of IGF2, as well as mechanisms of inducing dysplasia in vitro and tumorigenicity in vivo. We have tried to answer which molecular changes of the IGF2 gene and its regulatory mechanisms have the most significance in initiation, progression (including liver metastasis), prognosis, and potential anti-IGF2 therapy in CRC patients.
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Affiliation(s)
- Aldona Kasprzak
- Department of Histology and Embryology, University of Medical Sciences, Swiecicki Street 6, 60-781 Poznan, Poland.
| | - Agnieszka Adamek
- Department of Infectious Diseases, Hepatology and Acquired Immunodeficiencies, University of Medical Sciences, Szwajcarska Street 3, 61-285 Poznan, Poland.
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Hack NL, Cordova KL, Glaser FL, Journey ML, Resner EJ, Hardy KM, Beckman BR, Lema SC. Interactions of long-term food ration variation and short-term fasting on insulin-like growth factor-1 (IGF-1) pathways in copper rockfish (Sebastes caurinus). Gen Comp Endocrinol 2019; 280:168-184. [PMID: 31022390 DOI: 10.1016/j.ygcen.2019.04.025] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/15/2019] [Revised: 04/13/2019] [Accepted: 04/21/2019] [Indexed: 12/26/2022]
Abstract
Variation in food intake affects somatic growth by altering the expression of hormones in the somatotropic endocrine axis including insulin-like growth factor-1 (IGF-1). Here, we examined IGF-1 pathway responses to long- and short-term variation in food availability in copper rockfish (Sebastes caurinus), a nearshore Pacific rockfish important for commercial and recreational fisheries. Juvenile copper rockfish were raised under differing ration amounts (3% or 9% mass feed·g-1 fish wet mass·day-1) for 140 d to simulate 'long-term' feeding variation, after which some fish from both rations were fasted for 12 d to generate 'short-term' conditions of food deprivation. Rockfish on the 9% ration treatment grew more quickly than those on the 3% ration and were larger in mass, length, and body condition (k) after 152 d. Fish on the 9% ration had higher blood glucose than those on the 3% ration, with fasting decreasing blood glucose in both ration treatments, indicating that both long-term and short-term feed treatments altered energy status. Plasma IGF-1 was higher in rockfish from the 9% ration than those in the 3% ration and was also higher in fed fish than fasted fish. Additionally, plasma IGF-1 related positively to individual variation in specific growth rate (SGR). The positive association between IGF-1 and SGR showed discordance in fish that had experienced different levels of food and growth over the long-term but not short-term, suggesting that long-term nutritional experience can influence the relationship between IGF-1 and growth in this species. Rockfish on the 3% ration showed a lower relative abundance of gene transcripts encoding igf1 in the liver, but higher hepatic mRNAs for IGF binding proteins igfbp1a and igfbp1b. Fasting similarly decreased the abundance of igf1 mRNAs in the liver of fish reared under both the 9% and 3% rations, while concurrently increasing mRNAs encoding the IGF binding proteins igfbp1a, -1b, and -3a. Hepatic mRNAs for igfbp2b, -5a, and -5b were lower with long-term ration variation (3% ration) and fasting. Fish that experienced long-term reduced rations also had higher mRNA levels for igfbp3a, -3b, and IGF receptors isoforms A (igf1rA) and B (igf1rB) in skeletal muscle, but lower mRNA levels for igf1. Fasting increased muscle mRNA abundance for igfbp3a, igf1rA, and igf1rB, and decreased levels for igfbp2a and igf1. These data show that a positive relationship between circulating IGF-1 and individual growth rate is maintained in copper rockfish even when that growth variation relates to differences in food consumption across varying time scales, but that long- and short-term variation in food quantity can shift basal concentrations of circulating IGF-1 in this species.
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Affiliation(s)
- Nicole L Hack
- Biological Sciences Department, Center for Coastal Marine Sciences, California Polytechnic State University, San Luis Obispo, CA 93407, USA
| | - Kasey L Cordova
- Biological Sciences Department, Center for Coastal Marine Sciences, California Polytechnic State University, San Luis Obispo, CA 93407, USA
| | - Frances L Glaser
- Biological Sciences Department, Center for Coastal Marine Sciences, California Polytechnic State University, San Luis Obispo, CA 93407, USA
| | - Meredith L Journey
- Lynker Technology, 202 Church St SE #536, Leesburg, VA 20175, Under Contract to Environmental and Fisheries Sciences Division, Northwest Fisheries Science Center, National Marine Fisheries Service, National Oceanic and Atmospheric Administration, Seattle, WA 98112, USA
| | - Emily J Resner
- Biological Sciences Department, Center for Coastal Marine Sciences, California Polytechnic State University, San Luis Obispo, CA 93407, USA
| | - Kristin M Hardy
- Biological Sciences Department, Center for Coastal Marine Sciences, California Polytechnic State University, San Luis Obispo, CA 93407, USA
| | - Brian R Beckman
- Environmental and Fisheries Sciences Division, Northwest Fisheries Science Center, National Marine Fisheries Service, National Oceanic and Atmospheric Administration, Seattle, WA, 98112, USA
| | - Sean C Lema
- Biological Sciences Department, Center for Coastal Marine Sciences, California Polytechnic State University, San Luis Obispo, CA 93407, USA.
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Stoffel W, Hammels I, Jenke B, Schmidt-Soltau I, Niehoff A. Neutral Sphingomyelinase 2 (SMPD3) Deficiency in Mice Causes Chondrodysplasia with Unimpaired Skeletal Mineralization. THE AMERICAN JOURNAL OF PATHOLOGY 2019; 189:1831-1845. [PMID: 31199918 DOI: 10.1016/j.ajpath.2019.05.008] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/12/2018] [Revised: 05/10/2019] [Accepted: 05/14/2019] [Indexed: 10/26/2022]
Abstract
SMPD3 deficiency in the neutral sphingomyelinase (Smpd3-/-) mouse results in a novel form of juvenile dwarfism, suggesting smpd3 is a polygenetic determinant of body height. SMPD3 controls homeostasis of the sphingomyelin cycle in the Golgi compartment, essential for membrane remodeling, initiating multiform vesicle formation and transport in the Golgi secretory pathway. Using the unbiased Smpd3-/- genetic model, this study shows that the perturbed Golgi secretory pathway of chondrocytes of the epiphyseal growth zone leads to dysproteostasis, skeletal growth inhibition, malformation, and chondrodysplasia, but showed unimpaired mineralization in primary and secondary enchondral ossification centers. This has been elaborated by biochemical analyses and immunohistochemistry of long bones of Smpd3-/- mice. A more precise definition of the microarchitecture and three-dimensional structure of the bone was shown by peripheral quantitative computed tomography, high-resolution microcomputed tomography, and less precisely by dual-energy X-ray absorptiometry for osteodensitometry. Ablation of the Smpd3 locus as part of a 980-kb deletion on chromosome 8 in the fro/fro mutant, generated by chemical mutagenesis, is held responsible for skeletal hypomineralization, osteoporosis, and multiple fractures of long bones, which are hallmarks of human osteogenesis imperfecta. The phenotype of the genetically unbiased Smpd3-/- mouse, described here, precludes the proposed role of Smpd3 as a candidate gene of human osteogenesis imperfecta, but suggests SMPD3 deficiency as the pathogenetic basis of a novel form of chondrodysplasia.
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Affiliation(s)
- Wilhelm Stoffel
- Laboratory of Molecular Neurosciences, Center of Biochemistry, Faculty of Medicine, University of Cologne, Cologne, Germany; Center of Molecular Medicine, University of Cologne, Cologne, Germany; Cluster of Excellence, Cellular Stress Responses in Age Associated Diseases, University of Cologne, Cologne, Germany.
| | - Ina Hammels
- Laboratory of Molecular Neurosciences, Center of Biochemistry, Faculty of Medicine, University of Cologne, Cologne, Germany; Center of Molecular Medicine, University of Cologne, Cologne, Germany
| | - Britta Jenke
- Laboratory of Molecular Neurosciences, Center of Biochemistry, Faculty of Medicine, University of Cologne, Cologne, Germany; Center of Molecular Medicine, University of Cologne, Cologne, Germany
| | - Inga Schmidt-Soltau
- Laboratory of Molecular Neurosciences, Center of Biochemistry, Faculty of Medicine, University of Cologne, Cologne, Germany; Center of Molecular Medicine, University of Cologne, Cologne, Germany
| | - Anja Niehoff
- Institute of Biomechanics and Orthopedics, German Sport University Cologne, Cologne Center for Musculoskeletal Biomechanics, Faculty of Medicine, University of Cologne, Cologne, Germany
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20
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Tang X, Lan T, Wu R, Zhou Z, Chen Y, Sun Y, Zheng Y, Ma J. Analysis of long non-coding RNAs in neonatal piglets at different stages of porcine deltacoronavirus infection. BMC Vet Res 2019; 15:111. [PMID: 30971240 PMCID: PMC6458635 DOI: 10.1186/s12917-019-1862-4] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2018] [Accepted: 04/03/2019] [Indexed: 01/17/2023] Open
Abstract
BACKGROUND PDCoV (Porcine Deltacoronavirus) is a novel porcine coronavirus that causes intestinal necrosis of piglets, thinning of the intestinal wall and severe villus atrophy in the small intestine. PDCoV is a highly contagious infectious disease characterized by diarrhea, dehydration and vomiting. It has been reported that lncRNA has a significant effect on viral replication and increased or decreased virulence. At present, there is almost no research on lncRNA related to PDCoV infection. With the development of the research, a large number of lncRNAs related to PDCoV infection have been discovered. Identifying the role of these lncRNAs in the infection process facilitates the screening of diagnostically significant biomarkers. RESULTS Using high throughput sequencing to screen differentially expressed long non-coding RNA (lncRNA) during PDCoV infection, we identified 99, 41 and 33 differentially expressed lncRNAs in the early, middle and late stages of infection, respectively. These lncRNAs were involved in glycolysis / gluconeogenesis, histidine metabolism and pentose and Chloroalkane and chloroalkene degradation pathway. We obtained expression data of miRNAs, lncRNAs and mRNAs during PDCoV infection and constructed and investigated an interaction network. The qRT-PCR validation results of 6 differentially expressed lncRNAs were consistent with RNA-Seq results. CONCLUSIONS This study is the first to examine differentially expressed lncRNAs after PDCoV infection of piglets. These results can provide new insights into PDCoV infection and antiviral strategies.
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Affiliation(s)
- Xiaoyu Tang
- College of Animal Science, South China Agricultural University, Tianhe District, Wushan Road 483, Guangzhou, 510642, China.,Key Laboratory of Animal Health Aquaculture and Environmental Control, Guangzhou, Guangdong, China
| | - Tian Lan
- College of Animal Science, South China Agricultural University, Tianhe District, Wushan Road 483, Guangzhou, 510642, China.,Key Laboratory of Animal Health Aquaculture and Environmental Control, Guangzhou, Guangdong, China
| | - Ruiting Wu
- College of Animal Science, South China Agricultural University, Tianhe District, Wushan Road 483, Guangzhou, 510642, China.,Key Laboratory of Animal Health Aquaculture and Environmental Control, Guangzhou, Guangdong, China
| | - Zhihai Zhou
- College of Animal Science, South China Agricultural University, Tianhe District, Wushan Road 483, Guangzhou, 510642, China.,Key Laboratory of Animal Health Aquaculture and Environmental Control, Guangzhou, Guangdong, China
| | - Yuqi Chen
- College of Animal Science, South China Agricultural University, Tianhe District, Wushan Road 483, Guangzhou, 510642, China.,Key Laboratory of Animal Health Aquaculture and Environmental Control, Guangzhou, Guangdong, China
| | - Yuan Sun
- College of Animal Science, South China Agricultural University, Tianhe District, Wushan Road 483, Guangzhou, 510642, China.,Key Laboratory of Animal Health Aquaculture and Environmental Control, Guangzhou, Guangdong, China
| | - Yaoyao Zheng
- College of Animal Science, South China Agricultural University, Tianhe District, Wushan Road 483, Guangzhou, 510642, China.,Key Laboratory of Animal Health Aquaculture and Environmental Control, Guangzhou, Guangdong, China
| | - Jingyun Ma
- College of Animal Science, South China Agricultural University, Tianhe District, Wushan Road 483, Guangzhou, 510642, China. .,Key Laboratory of Animal Health Aquaculture and Environmental Control, Guangzhou, Guangdong, China.
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21
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Meyer KF, Verkaik-Schakel RN, Timens W, Kobzik L, Plösch T, Hylkema MN. The fetal programming effect of prenatal smoking on Igf1r and Igf1 methylation is organ- and sex-specific. Epigenetics 2018; 12:1076-1091. [PMID: 29160127 PMCID: PMC5810788 DOI: 10.1080/15592294.2017.1403691] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022] Open
Abstract
The impact of prenatal smoke exposure (PSE) on DNA methylation has been demonstrated in blood samples from children of smoking mothers, but evidence for sex-dependent smoke-induced effects is limited. As the identified differentially methylated genes can be associated with developmental processes, and insulin-like growth factors (IGFs) play a critical role in prenatal tissue growth, we hypothesized that PSE induces fetal programming of Igf1r and Igf1. Using a mouse model of smoking during pregnancy, we show that PSE alters promoter methylation of Igf1r and Igf1 and deregulates their gene expression in lung and liver of fetal (E17.5) and neonatal (D3) mouse offspring. By further comparing female versus male, lung versus liver, or fetal versus neonatal time point, our results demonstrate that CpG site-specific aberrant methylation patterns sex-dependently vary per organ and time point. Moreover, PSE reduces gene expression of Igf1r and Igf1, dependent on organ, sex, and offspring's age. Our results indicate that PSE may be a source of organ-specific rather than general systemic fetal programming. This is exemplified here by gene promoter methylation and mRNA levels of Igf1r and Igf1, together with a sex- and organ-specific naturally established correlation of both parameters that is affected by prenatal smoke exposure. Moreover, the comparison of fetuses with neonates suggests a CpG site-dependent reversibility/persistence of PSE-induced differential methylation patterns.
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Affiliation(s)
- Karolin F Meyer
- a Department of Pathology and Medical Biology , University of Groningen, University Medical Center Groningen , Hanzeplein 1, EA10, 9713 GZ , Groningen , The Netherlands.,b University of Groningen , University Medical Center Groningen , GRIAC Research Institute , Hanzeplein 1, EA10, 9713 GZ , Groningen , The Netherlands
| | - Rikst Nynke Verkaik-Schakel
- c Department of Obstetrics and Gynaecology , University of Groningen , University Medical Center Groningen , Hanzeplein 1, 9713 GZ , Groningen , The Netherlands
| | - Wim Timens
- a Department of Pathology and Medical Biology , University of Groningen, University Medical Center Groningen , Hanzeplein 1, EA10, 9713 GZ , Groningen , The Netherlands.,b University of Groningen , University Medical Center Groningen , GRIAC Research Institute , Hanzeplein 1, EA10, 9713 GZ , Groningen , The Netherlands
| | - Lester Kobzik
- d Molecular and Integrative Physiological Sciences Program, Department of Environmental Health , Harvard T. H. Chan School of Public Health , Building II Room 221, 655 Huntington Avenue, Boston , MA 02115 , USA
| | - Torsten Plösch
- c Department of Obstetrics and Gynaecology , University of Groningen , University Medical Center Groningen , Hanzeplein 1, 9713 GZ , Groningen , The Netherlands
| | - Machteld N Hylkema
- a Department of Pathology and Medical Biology , University of Groningen, University Medical Center Groningen , Hanzeplein 1, EA10, 9713 GZ , Groningen , The Netherlands.,b University of Groningen , University Medical Center Groningen , GRIAC Research Institute , Hanzeplein 1, EA10, 9713 GZ , Groningen , The Netherlands
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22
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Heinen A, Nederlof R, Panjwani P, Spychala A, Tschaidse T, Reffelt H, Boy J, Raupach A, Gödecke S, Petzsch P, Köhrer K, Grandoch M, Petz A, Fischer JW, Alter C, Vasilevska J, Lang P, Gödecke A. IGF1 Treatment Improves Cardiac Remodeling after Infarction by Targeting Myeloid Cells. Mol Ther 2018; 27:46-58. [PMID: 30528085 DOI: 10.1016/j.ymthe.2018.10.020] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2018] [Revised: 10/25/2018] [Accepted: 10/26/2018] [Indexed: 12/20/2022] Open
Abstract
Insulin-like growth factor 1 (IGF1) is an anabolic hormone that controls the growth and metabolism of many cell types. However, IGF1 also mediates cardio-protective effects after acute myocardial infarction (AMI), but the underlying mechanisms and cellular targets are not fully understood. Here we demonstrate that short-term IGF1 treatment for 3 days after AMI improved cardiac function after 1 and 4 weeks. Regional wall motion was improved in ischemic segments, scar size was reduced, and capillary density increased in the infarcted area and the border zone. Unexpectedly, inducible inactivation of the IGF1 receptor (IGF1R) in cardiomyocytes did not attenuate the protective effect of IGF1. Sequential cardiac transcriptomic analysis indicated an altered myeloid cell response in the acute phase after AMI, and, notably, myeloid-cell Igf1r-/- mice lost the protective IGF1 function after I/R. In addition, IGF1 induced an M2-like anti-inflammatory phenotype in bone marrow-derived macrophages and enhanced the number of anti-inflammatory macrophages in heart tissue on day 3 after AMI in vivo. In summary, modulation of the acute inflammatory phase after AMI by IGF1 represents an effective mechanism to preserve cardiac function after I/R.
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Affiliation(s)
- Andre Heinen
- Institut für Herz- und Kreislaufphysiologie, Heinrich-Heine-Universität Düsseldorf, 40225 Düsseldorf, Germany
| | - Rianne Nederlof
- Institut für Herz- und Kreislaufphysiologie, Heinrich-Heine-Universität Düsseldorf, 40225 Düsseldorf, Germany
| | - Priyadarshini Panjwani
- Institut für Herz- und Kreislaufphysiologie, Heinrich-Heine-Universität Düsseldorf, 40225 Düsseldorf, Germany
| | - André Spychala
- Institut für Herz- und Kreislaufphysiologie, Heinrich-Heine-Universität Düsseldorf, 40225 Düsseldorf, Germany
| | - Tengis Tschaidse
- Institut für Herz- und Kreislaufphysiologie, Heinrich-Heine-Universität Düsseldorf, 40225 Düsseldorf, Germany
| | - Heiko Reffelt
- Institut für Herz- und Kreislaufphysiologie, Heinrich-Heine-Universität Düsseldorf, 40225 Düsseldorf, Germany
| | - Johannes Boy
- Institut für Herz- und Kreislaufphysiologie, Heinrich-Heine-Universität Düsseldorf, 40225 Düsseldorf, Germany
| | - Annika Raupach
- Institut für Herz- und Kreislaufphysiologie, Heinrich-Heine-Universität Düsseldorf, 40225 Düsseldorf, Germany
| | - Stefanie Gödecke
- Institut für Herz- und Kreislaufphysiologie, Heinrich-Heine-Universität Düsseldorf, 40225 Düsseldorf, Germany
| | - Patrick Petzsch
- Biologisch-Medizinisches Forschungszentrum (BMFZ), Genomics and Transcriptomics Labor, Heinrich-Heine-Universität Düsseldorf, 40225 Düsseldorf, Germany
| | - Karl Köhrer
- Biologisch-Medizinisches Forschungszentrum (BMFZ), Genomics and Transcriptomics Labor, Heinrich-Heine-Universität Düsseldorf, 40225 Düsseldorf, Germany
| | - Maria Grandoch
- Institut für Pharmakologie und Klinische Pharmakologie, Heinrich-Heine-Universität Düsseldorf, 40225 Düsseldorf, Germany
| | - Anne Petz
- Institut für Pharmakologie und Klinische Pharmakologie, Heinrich-Heine-Universität Düsseldorf, 40225 Düsseldorf, Germany
| | - Jens W Fischer
- Institut für Pharmakologie und Klinische Pharmakologie, Heinrich-Heine-Universität Düsseldorf, 40225 Düsseldorf, Germany
| | - Christina Alter
- Institut für Molekulare Kardiologie, Heinrich-Heine-Universität Düsseldorf, 40225 Düsseldorf, Germany
| | - Jelena Vasilevska
- Institut für Molekulare Medizin II, Heinrich-Heine-Universität Düsseldorf, 40225 Düsseldorf, Germany
| | - Philipp Lang
- Institut für Molekulare Medizin II, Heinrich-Heine-Universität Düsseldorf, 40225 Düsseldorf, Germany
| | - Axel Gödecke
- Institut für Herz- und Kreislaufphysiologie, Heinrich-Heine-Universität Düsseldorf, 40225 Düsseldorf, Germany.
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Hack NL, Strobel JS, Journey ML, Beckman BR, Lema SC. Response of the insulin-like growth factor-1 (Igf1) system to nutritional status and growth rate variation in olive rockfish (Sebastes serranoides). Comp Biochem Physiol A Mol Integr Physiol 2018; 224:42-52. [DOI: 10.1016/j.cbpa.2018.05.025] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2018] [Revised: 05/28/2018] [Accepted: 05/30/2018] [Indexed: 12/20/2022]
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Chen W, Lin H, Li W. Molecular cloning and expression profiles of IGFBP-1a in common carp (Cyprinus carpio) and its expression regulation by growth hormone in hepatocytes. Comp Biochem Physiol B Biochem Mol Biol 2018; 221-222:50-59. [PMID: 29698715 DOI: 10.1016/j.cbpb.2018.04.005] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2017] [Revised: 04/06/2018] [Accepted: 04/16/2018] [Indexed: 11/16/2022]
Abstract
In this study, we cloned and determined IGFBP-1a cDNA from common carp (Cyprinus carpio) liver. The 1655 bp full-length cDNA consisted of a 96 bp 5-untranslated region (UTR), a 789 bp open reading frame encoding 262 amino acid residues and a 770 bp 3-UTR containing seven mRNA instability motifs. Northern blot revealed a 1.8 kb IGFBP-1a transcript. IGFBP-1a mRNA was widely distributed in all tissues examined and predominantly expressed in the liver. During embryogenesis, IGFBP-1a mRNA was firstly observed in blastula stage, and significant increases were observed in body segment stage, lens formation stage and blood cycling stage. After hatching, its expression increased more than twenty times. Furthermore, hypoxia could significantly up-regulate IGFBP-1a expression in the liver and brain. IGFBP-1a expression increased with ovarian maturation and decreased at regressed stage. In testis, IGFBP-1a mRNA maintained relatively higher levels at recrudescing and matured stages, while it sharply declined at regressed stage. In primary cultured hepatocytes, IGFBP-1a gene was greatly down-regulated by growth hormone via the MAPK and PI3 kinase signaling pathways. These results suggest that IGFBP-1a may be involved in the IGF system regulating growth, development and reproduction in common carp.
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Affiliation(s)
- Wenbo Chen
- State Key Laboratory of Biocontrol, Institute of Aquatic Economic Animals and Guangdong Provincial Key Laboratory for Aquatic Economic Animals, Guangdong Provincial Engineering Technology Research Center for Healthy Breeding of Important Economic Fish, School of Life Sciences, Sun Yat-Sen University, Guangzhou 510275, China; Department of Biology, Institute of Resources and Environment, Henan Polytechnic University, Jiaozuo 454000, China
| | - Haoran Lin
- State Key Laboratory of Biocontrol, Institute of Aquatic Economic Animals and Guangdong Provincial Key Laboratory for Aquatic Economic Animals, Guangdong Provincial Engineering Technology Research Center for Healthy Breeding of Important Economic Fish, School of Life Sciences, Sun Yat-Sen University, Guangzhou 510275, China
| | - Wensheng Li
- State Key Laboratory of Biocontrol, Institute of Aquatic Economic Animals and Guangdong Provincial Key Laboratory for Aquatic Economic Animals, Guangdong Provincial Engineering Technology Research Center for Healthy Breeding of Important Economic Fish, School of Life Sciences, Sun Yat-Sen University, Guangzhou 510275, China.
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Oh HS, Oh SK, Lee JS, Wu C, Lee SJ. Effects of l-arginine on growth hormone and insulin-like growth factor 1. Food Sci Biotechnol 2017; 26:1749-1754. [PMID: 30263714 DOI: 10.1007/s10068-017-0236-6] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2017] [Revised: 07/03/2017] [Accepted: 07/05/2017] [Indexed: 10/18/2022] Open
Abstract
l-Arginine has been reported to promote cellular and organismal growth. In this study, the effects of l-arginine on the expression of growth hormone (GH) and insulin-like growth factor 1 (IGF-1), the two key growth factors, are investigated in cultured GH3 pituitary epithelium and HepG2 cells, respectively. l-Arginine significantly induced the gene expression of GH and IGF-1 in GH3 pituitary epithelium and HepG2 hepatocytes respectively, and reduced IGF binding protein-1 gene expression in HepG2 cells assessed via quantitative polymerase chain reaction analysis. l-Arginine also significantly induced GH and IGF-1 hormone secretion from GH3 and HepG2 cells, respectively. In addition, the multi-target ELISA analysis conducted revealed that phosphorylation of p-38 MAPK, MEK, and JNK were significantly increased in HepG2 cells, suggesting l-arginine-induced activation of the MAPK signaling pathway. These results suggest that l-arginine promotes the synthesis and secretion of GH and IGF-1 in vitro and induces the MAPK signaling cascade in cultured hepatocytes.
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Affiliation(s)
- Hyun-Seok Oh
- 1Department of Biotechnology, School of Life Sciences and Biotechnology for BK21 PLUS, Korea University, Seoul, 02841 Korea
| | - Se Kwan Oh
- 2Rice Research Division, National Institute of Crop Science, Rural Development Administration, Suwon, 441-857 Korea
| | - Jum Seek Lee
- 2Rice Research Division, National Institute of Crop Science, Rural Development Administration, Suwon, 441-857 Korea
| | - Chunyan Wu
- 1Department of Biotechnology, School of Life Sciences and Biotechnology for BK21 PLUS, Korea University, Seoul, 02841 Korea
| | - Sung-Joon Lee
- 1Department of Biotechnology, School of Life Sciences and Biotechnology for BK21 PLUS, Korea University, Seoul, 02841 Korea
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Impaired insulin/IGF-1 is responsible for diabetic gastroparesis by damaging myenteric cholinergic neurones and interstitial cells of Cajal. Biosci Rep 2017; 37:BSR20170776. [PMID: 28931726 PMCID: PMC5665615 DOI: 10.1042/bsr20170776] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2017] [Revised: 09/14/2017] [Accepted: 09/17/2017] [Indexed: 02/06/2023] Open
Abstract
Diabetic gastroparesis is a common complication of diabetes mellitus (DM) that is characterized by decreased serum insulin and insulin-like growth factor-1 (IGF-1). Despite the fact that insulin treatment not glycemic control potently accelerated gastric emptying in type 1 DM patients, the role of insulin/InsR and IGF-1/IGF-1R signaling in diabetic gastroparesis remains incompletely elucidated. In the present study, type 1 DM mice were established and treated with insulin or Voglibose for 8 weeks. The gastric emptying was delayed from DM week 4 when the gastric InsR and IGF-1R were declined. Meanwhile, the gastric choline acetyltransferase (ChAT) was significantly reduced and the myenteric cholinergic neurones and their fibers were significantly diminished. The production of stem cell factor (SCF) was dramatically repressed in the gastric smooth muscles in DM week 6. TWereafter, interstitial cells of Cajal (ICC) were clearly lost and their networks were impaired in DM week 8. Significantly, compared with Voglibose, an 8-week treatment with insulin more efficiently delayed diabetic gastroparesis development by protecting the myenteric cholinergic neurones and ICC. In conclusion, diabetic gastroparesis was an aggressive process due to the successive damages of myenteric cholinergic neurones and ICC by impairing the insulin/InsR and IGF-1/IGF-1R signaling. Insulin therapy in the early stage may delay diabetic gastroparesis.
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27
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Yi MJ, Park TY, Hwang IT, Yang S. Influence of The -202 A/C insulin-like growth factor-binding protein-3 promoter polymorphism on individual variation in height in Korean girls. Ann Pediatr Endocrinol Metab 2017; 22:36-42. [PMID: 28443257 PMCID: PMC5401820 DOI: 10.6065/apem.2017.22.1.36] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/05/2016] [Revised: 08/29/2016] [Accepted: 09/20/2016] [Indexed: 11/20/2022] Open
Abstract
PURPOSE The most common single nucleotide polymorphism in the IGFBP3 promoter region occurs at position -202. This polymorphic variation occurs frequently and may influence growth hormone responsiveness and somatic growth. However, the effects of IGFBP3 promoter polymorphism on growth in children are unknown. METHODS Restriction fragment length polymorphism-based genotyping of the -202 single nucleotide polymorphism was performed in 146 Korean girls aged between 15 and 16 years, who were selected randomly from the Seoul School Health Promotion Center. The participants were divided into 3 groups (tall, medium, and short) according to the height percentile established from normal reference values for Korean children. The serum levels of insulin-like growth factor I (IGF-I) and IGF-binding protein-3 (IGFBP-3) were then compared according to genotype. RESULTS The genotype distribution in the participants was 79 AA (54.1%), 60 AC (41.1%), and 7 CC (4.8%). The C allele frequency at the -202 IGFBP3 position was 25.4% in this group. The mean serum IGFBP-3 concentration in girls with the AA genotype was higher than that in girls with the AC genotype in the medium (P=0.047) and short (P=0.035) groups, respectively. There was no difference in the IGF-I to IGFBP-3 molar ratio between the AA and AC genotype groups (P=0.161). CONCLUSION In conclusion, the -202 polymorphism in the IGFBP3 promoter region is assumed to affect the serum concentration of IGFBP-3 in children as well as in adults. However, it is unclear whether this affects physical development according to the concentration of IGFBP-3.
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Affiliation(s)
- Min Ju Yi
- Department of Pediatrics, Hallym University College of Medicine, Seoul, Korea
| | - Tae Young Park
- Department of Pediatrics, Hallym University College of Medicine, Seoul, Korea
| | - Il Tae Hwang
- Department of Pediatrics, Hallym University College of Medicine, Seoul, Korea
| | - Seung Yang
- Department of Pediatrics, Hallym University College of Medicine, Seoul, Korea
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The Roles of Insulin-Like Growth Factors in Mesenchymal Stem Cell Niche. Stem Cells Int 2017; 2017:9453108. [PMID: 28298931 PMCID: PMC5337393 DOI: 10.1155/2017/9453108] [Citation(s) in RCA: 50] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2016] [Revised: 12/22/2016] [Accepted: 01/18/2017] [Indexed: 12/12/2022] Open
Abstract
Many tissues contain adult mesenchymal stem cells (MSCs), which may be used in tissue regeneration therapies. However, the MSC availability in most tissues is limited which demands expansion in vitro following isolation. Like many developing cells, the state of MSCs is affected by the surrounding microenvironment, and mimicking this natural microenvironment that supports multipotent or differentiated state in vivo is essential to understand for the successful use of MSC in regenerative therapies. Many researchers are, therefore, optimizing cell culture conditions in vitro by altering growth factors, extracellular matrices, chemicals, oxygen tension, and surrounding pH to enhance stem cells self-renewal or differentiation. Insulin-like growth factors (IGFs) system has been demonstrated to play an important role in stem cell biology to either promote proliferation and self-renewal or enhance differentiation onset and outcome, depending on the cell culture conditions. In this review, we will describe the importance of IGFs, IGF-1 and IGF-2, in development and in the MSC niche and how they affect the pluripotency or differentiation towards multiple lineages of the three germ layers.
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Pareek AS, Garger YB, Joshi PM, Romero CM, Seth AK. Secondary Causes of Diabetes Mellitus. PRINCIPLES OF DIABETES MELLITUS 2017:311-326. [DOI: 10.1007/978-3-319-18741-9_16] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/05/2025]
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Abstract
The skeletal muscle mass is known to be controlled by the balance between protein synthesis and degradation. The fractional rate of protein synthesis has been reported to decrease age-dependently from 1 to 4 weeks of age in the chicken breast muscle (pectoralis major muscle). On the other hand, age-dependent change of the fractional protein degradation rate was reported to be less in the skeletal muscle of chickens. These findings suggest that protein synthesis is age-dependently downregulated in chicken muscle. We herein investigated the age-dependent changes in protein synthesis or proteolysis-related factors in the breast muscle of 7, 14, 28, and 49-day old broiler chickens. IGF-1 mRNA level, phosphorylation rate of Akt, and phospho-S6 content were coordinately decreased in an age-dependent manner, suggesting that IGF-1-stimulated protein synthesis is downregulated with age in chicken breast muscle. In contrast, atrogin-1, one of the proteolysis-related factors, gradually increased with age at mRNA levels. However, plasma Nτ-methylhistidine concentration, an indicator of skeletal muscle proteolysis, did not coordinately change with atrogin-1 mRNA levels. Taken together, our results suggest that the IGF-1/Akt/S6 signaling pathway is age-dependently downregulated in the chicken breast muscle.
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31
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Breves JP, Phipps-Costin SK, Fujimoto CK, Einarsdottir IE, Regish AM, Björnsson BT, McCormick SD. Hepatic insulin-like growth-factor binding protein (igfbp) responses to food restriction in Atlantic salmon smolts. Gen Comp Endocrinol 2016; 233:79-87. [PMID: 27210270 DOI: 10.1016/j.ygcen.2016.05.015] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/01/2016] [Revised: 04/29/2016] [Accepted: 05/11/2016] [Indexed: 12/21/2022]
Abstract
The growth hormone (Gh)/insulin-like growth-factor (Igf) system plays a central role in the regulation of growth in fishes. However, the roles of Igf binding proteins (Igfbps) in coordinating responses to food availability are unresolved, especially in anadromous fishes preparing for seaward migration. We assayed plasma Gh, Igf1, thyroid hormones and cortisol along with igfbp mRNA levels in fasted and fed Atlantic salmon (Salmo salar). Fish were fasted for 3 or 10days near the peak of smoltification (late April to early May). Fasting reduced plasma glucose by 3days and condition factor by 10days. Plasma Gh, cortisol, and thyroxine (T4) were not altered in response to fasting, whereas Igf1 and 3,5,3'-triiodo-l-thyronine (T3) were slightly higher and lower than controls, respectively. Hepatic igfbp1b1, -1b2, -2a, -2b1 and -2b2 mRNA levels were not responsive to fasting, but there were marked increases in igfbp1a1 following 3 and 10days of fasting. Fasting did not alter hepatic igf1 or igf2; however, muscle igf1 was diminished by 10days of fasting. There were no signs that fasting compromised branchial ionoregulatory functions, as indicated by unchanged Na(+)/K(+)-ATPase activity and ion pump/transporter mRNA levels. We conclude that dynamic hepatic igfbp1a1 and muscle igf1 expression participate in the modulation of Gh/Igf signaling in smolts undergoing catabolism.
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Affiliation(s)
- Jason P Breves
- Department of Biology, Skidmore College, 815 N. Broadway, Saratoga Springs, NY 12866, USA.
| | - Silas K Phipps-Costin
- Department of Biology, Skidmore College, 815 N. Broadway, Saratoga Springs, NY 12866, USA
| | - Chelsea K Fujimoto
- Department of Biology, Skidmore College, 815 N. Broadway, Saratoga Springs, NY 12866, USA
| | - Ingibjörg E Einarsdottir
- Fish Endocrinology Laboratory, Department of Biological and Environmental Sciences, University of Gothenburg, Box 463, SE-40530 Göteborg, Sweden
| | - Amy M Regish
- USGS, Conte Anadromous Fish Research Center, P.O. Box 796, One Migratory Way, Turners Falls, MA 01376, USA
| | - Björn Thrandur Björnsson
- Fish Endocrinology Laboratory, Department of Biological and Environmental Sciences, University of Gothenburg, Box 463, SE-40530 Göteborg, Sweden
| | - Stephen D McCormick
- USGS, Conte Anadromous Fish Research Center, P.O. Box 796, One Migratory Way, Turners Falls, MA 01376, USA
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32
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Campos C, Rocha NBF, Lattari E, Paes F, Nardi AE, Machado S. Exercise-induced neuroprotective effects on neurodegenerative diseases: the key role of trophic factors. Expert Rev Neurother 2016; 16:723-34. [PMID: 27086703 DOI: 10.1080/14737175.2016.1179582] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
Age-related neurodegenerative disorders, like Alzheimer's or Parkinson's disease, are becoming a major issue to public health care. Currently, there is no effective pharmacological treatment to address cognitive impairment in these patients. Here, we aim to explore the role of exercise-induced trophic factor enhancement in the prevention or delay of cognitive decline in patients with neurodegenerative diseases. There is a significant amount of evidence from animal and human studies that links neurodegenerative related cognitive deficits with changes on brain and peripheral trophic factor levels. Several trials with elderly individuals and patients with neurodegenerative diseases report exercise induced cognitive improvements and changes on trophic factor levels including BDNF, IGF-I, among others. Further studies with healthy aging and clinical populations are needed to understand how diverse exercise interventions produce different variations in trophic factor signaling. Genetic profiles and potential confounders regarding trophic factors should also be addressed in future trials.
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Affiliation(s)
- Carlos Campos
- a Laboratory of Panic and Respiration , Institute of Psychiatry of Federal University of Rio de Janeiro (IPUB/UFRJ) , Rio de Janeiro , Brazil.,b School of Allied Health Sciences , Polytechnic Institute of Porto , Porto , Portugal
| | - Nuno Barbosa F Rocha
- b School of Allied Health Sciences , Polytechnic Institute of Porto , Porto , Portugal
| | - Eduardo Lattari
- a Laboratory of Panic and Respiration , Institute of Psychiatry of Federal University of Rio de Janeiro (IPUB/UFRJ) , Rio de Janeiro , Brazil
| | - Flávia Paes
- a Laboratory of Panic and Respiration , Institute of Psychiatry of Federal University of Rio de Janeiro (IPUB/UFRJ) , Rio de Janeiro , Brazil
| | - António E Nardi
- a Laboratory of Panic and Respiration , Institute of Psychiatry of Federal University of Rio de Janeiro (IPUB/UFRJ) , Rio de Janeiro , Brazil
| | - Sérgio Machado
- a Laboratory of Panic and Respiration , Institute of Psychiatry of Federal University of Rio de Janeiro (IPUB/UFRJ) , Rio de Janeiro , Brazil.,c Physical Activity Neuroscience Laboratory , Physical Activity Sciences Postgraduate Program - Salgado de Oliveira University (UNIVERSO) , Niterói , Brazil
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Ontsouka EC, Albrecht C, Bruckmaier RM. Invited review: Growth-promoting effects of colostrum in calves based on interaction with intestinal cell surface receptors and receptor-like transporters. J Dairy Sci 2016; 99:4111-4123. [PMID: 26874414 DOI: 10.3168/jds.2015-9741] [Citation(s) in RCA: 51] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2015] [Accepted: 12/28/2015] [Indexed: 12/13/2022]
Abstract
The postnatal development and maturation of the gastrointestinal (GI) tract of neonatal calves is crucial for their survival. Major morphological and functional changes in the calf's GI tract initiated by colostrum bioactive substances promote the establishment of intestinal digestion and absorption of food. It is generally accepted that colostrum intake provokes the maturation of organs and systems in young calves, illustrating the significance of the cow-to-calf connection at birth. These postnatal adaptive changes of the GI tissues in neonatal calves are especially induced by the action of bioactive substances such as insulin-like growth factors, hormones, or cholesterol carriers abundantly present in colostrum. These substances interact with specific cell-surface receptors or receptor-like transporters expressed in the GI wall of neonatal calves to elicit their biological effects. Therefore, the abundance and activity of cell surface receptors and receptor-like transporters binding colostral bioactive substances are a key aspect determining the effects of the cow-to-calf connection at birth. The present review compiles the information describing the effects of colostrum feeding on selected serum metabolic and endocrine traits in neonatal calves. In this context, the current paper discusses specifically the consequences of colostrum feeding on the GI expression and activity of cell-receptors and receptor-like transporters binding growth hormone, insulin-like growth factors, insulin, or cholesterol acceptors in neonatal calves.
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Affiliation(s)
- Edgar C Ontsouka
- Institute of Biochemistry and Molecular Medicine, Faculty of Medicine, University of Bern, CH-3012 Bern, Switzerland; Swiss National Center of Competence in Research, NCCR TransCure, University of Bern, CH-3012 Bern, Switzerland.
| | - Christiane Albrecht
- Institute of Biochemistry and Molecular Medicine, Faculty of Medicine, University of Bern, CH-3012 Bern, Switzerland; Swiss National Center of Competence in Research, NCCR TransCure, University of Bern, CH-3012 Bern, Switzerland
| | - Rupert M Bruckmaier
- Veterinary Physiology, Vetsuisse Faculty, University of Bern, CH-3012 Bern, Switzerland
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Saneyasu T, Kimura S, Inui M, Yoshimoto Y, Honda K, Kamisoyama H. Differences in the expression of genes involved in skeletal muscle proteolysis between broiler and layer chicks during food deprivation. Comp Biochem Physiol B Biochem Mol Biol 2015; 186:36-42. [DOI: 10.1016/j.cbpb.2015.04.007] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2014] [Revised: 04/03/2015] [Accepted: 04/12/2015] [Indexed: 01/01/2023]
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35
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Jeanplong F, Osepchook CC, Falconer SJ, Smith HK, Bass JJ, McMahon CD, Oldham JM. Undernutrition regulates the expression of a novel splice variant of myostatin and insulin-like growth factor 1 in ovine skeletal muscle. Domest Anim Endocrinol 2015; 52:17-24. [PMID: 25700268 DOI: 10.1016/j.domaniend.2015.01.002] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/30/2014] [Revised: 01/12/2015] [Accepted: 01/12/2015] [Indexed: 10/24/2022]
Abstract
Undernutrition suppresses the growth of skeletal muscles and alters the expression of insulin-like growth factor 1 (IGF1), a key mitogen, and myostatin, a potent inhibitor of myogenesis. These changes can explain, at least in part, the reduced growth of skeletal muscles in underfed lambs. We have recently identified a myostatin splice variant (MSV) that binds to and antagonizes the canonical signaling of myostatin. In the present study, we hypothesized that the expression of MSV would be reduced in conjunction with myostatin and IGF1 in response to underfeeding in skeletal muscles of sheep. Young growing ewes were fed either ad libitum or an energy-restricted diet (30% of maintenance requirements) for 28 d. This regime of underfeeding resulted in a 24% reduction in body mass (P < 0.001) and a 36% reduction in the mass of the semitendinosus muscles relative to controls (P < 0.001) by day 28. The concentrations of MSV and IGF1 messenger RNA (mRNA) were reduced (both P < 0.001), but myostatin mRNA was not altered in semitendinosus muscles. Unlike the reduced expression of mRNA, the abundance of MSV protein was increased (P < 0.05) and there was no change in the abundance of myostatin protein. Our results suggest that undernutrition for 28 d decreases the signaling of myostatin by increasing the abundance of MSV protein. Although this action may reduce the growth inhibitory activity of myostatin, it cannot prevent the loss of growth of skeletal muscles during undernutrition.
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Affiliation(s)
- F Jeanplong
- AgResearch Ltd, Ruakura Research Centre, Hamilton 3240, New Zealand.
| | - C C Osepchook
- AgResearch Ltd, Ruakura Research Centre, Hamilton 3240, New Zealand; Department of Sport and Exercise Science, University of Auckland, Auckland, New Zealand
| | - S J Falconer
- AgResearch Ltd, Ruakura Research Centre, Hamilton 3240, New Zealand
| | - H K Smith
- Department of Sport and Exercise Science, University of Auckland, Auckland, New Zealand
| | - J J Bass
- AgResearch Ltd, Ruakura Research Centre, Hamilton 3240, New Zealand; Liggins Institute, University of Auckland, Auckland, New Zealand
| | - C D McMahon
- AgResearch Ltd, Ruakura Research Centre, Hamilton 3240, New Zealand
| | - J M Oldham
- AgResearch Ltd, Ruakura Research Centre, Hamilton 3240, New Zealand
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36
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Fukushima T, Yoshihara H, Furuta H, Kamei H, Hakuno F, Luan J, Duan C, Saeki Y, Tanaka K, Iemura SI, Natsume T, Chida K, Nakatsu Y, Kamata H, Asano T, Takahashi SI. Nedd4-induced monoubiquitination of IRS-2 enhances IGF signalling and mitogenic activity. Nat Commun 2015; 6:6780. [PMID: 25879670 DOI: 10.1038/ncomms7780] [Citation(s) in RCA: 58] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2014] [Accepted: 02/26/2015] [Indexed: 01/02/2023] Open
Abstract
Insulin-like growth factors (IGFs) induce proliferation of various cell types and play important roles in somatic growth and cancer development. Phosphorylation of insulin receptor substrate (IRS)-1/2 by IGF-I receptor tyrosine kinase is essential for IGF action. Here we identify Nedd4 as an IRS-2 ubiquitin ligase. Nedd4 monoubiquitinates IRS-2, which promotes its association with Epsin1, a ubiquitin-binding protein. Nedd4 recruits IRS-2 to the membrane, probably through promoting Epsin1 binding, and enhances IGF-I receptor-induced IRS-2 tyrosine phosphorylation. In thyroid FRTL-5 cells, activation of the cyclic AMP pathway increases the association of Nedd4 with IRS-2, thereby enhancing IRS-2-mediated signalling and cell proliferation induced by IGF-I. The Nedd4 and IRS-2 association is also required for maximal activation of IGF-I signalling and cell proliferation in prostate cancer PC-3 cells. Nedd4 overexpression accelerates zebrafish embryonic growth through IRS-2 in vivo. We conclude that Nedd4-induced monoubiquitination of IRS-2 enhances IGF signalling and mitogenic activity.
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Affiliation(s)
- Toshiaki Fukushima
- 1] Department of Animal Sciences and Applied Biological Chemistry, Graduate School of Agriculture and Life Sciences, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-8657, Japan [2] Department of Medical Science, Graduate School of Medicine, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima City, Hiroshima 734-8553, Japan
| | - Hidehito Yoshihara
- 1] Department of Animal Sciences and Applied Biological Chemistry, Graduate School of Agriculture and Life Sciences, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-8657, Japan [2] Laboratory of Protein Metabolism, Tokyo Metropolitan Institute of Medical Science, 2-1-6 Kamikitazawa, Setagaya-ku, Tokyo 156-8506, Japan
| | - Haruka Furuta
- Department of Animal Sciences and Applied Biological Chemistry, Graduate School of Agriculture and Life Sciences, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-8657, Japan
| | - Hiroyasu Kamei
- Department of Animal Sciences and Applied Biological Chemistry, Graduate School of Agriculture and Life Sciences, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-8657, Japan
| | - Fumihiko Hakuno
- Department of Animal Sciences and Applied Biological Chemistry, Graduate School of Agriculture and Life Sciences, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-8657, Japan
| | - Jing Luan
- Key Laboratory of Marine Drugs, Chinese Ministry of Education, Ocean University of China, 5 Yushan Road, Qingdao, Shandong 266003, China
| | - Cunming Duan
- Department of Molecular, Cellular and Developmental Biology, University of Michigan, 830 North University, Ann Arbor, Michigan 48109, USA
| | - Yasushi Saeki
- Laboratory of Protein Metabolism, Tokyo Metropolitan Institute of Medical Science, 2-1-6 Kamikitazawa, Setagaya-ku, Tokyo 156-8506, Japan
| | - Keiji Tanaka
- Laboratory of Protein Metabolism, Tokyo Metropolitan Institute of Medical Science, 2-1-6 Kamikitazawa, Setagaya-ku, Tokyo 156-8506, Japan
| | - Shun-Ichiro Iemura
- Translational Research Center, Fukushima Medical University, 11-25 Sakaemachi, Fukushima City, Fukushima 960-8031, Japan
| | - Tohru Natsume
- Molecular Profiling Research Center for Drug Discovery (molprof), National Institute of Advanced Industrial Science and Technology (AIST), 2-4-7 Aomi, Koto-ku, Tokyo 135-0064, Japan
| | - Kazuhiro Chida
- Department of Animal Sciences and Applied Biological Chemistry, Graduate School of Agriculture and Life Sciences, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-8657, Japan
| | - Yusuke Nakatsu
- Department of Medical Science, Graduate School of Medicine, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima City, Hiroshima 734-8553, Japan
| | - Hideaki Kamata
- Department of Medical Science, Graduate School of Medicine, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima City, Hiroshima 734-8553, Japan
| | - Tomoichiro Asano
- Department of Medical Science, Graduate School of Medicine, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima City, Hiroshima 734-8553, Japan
| | - Shin-Ichiro Takahashi
- Department of Animal Sciences and Applied Biological Chemistry, Graduate School of Agriculture and Life Sciences, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-8657, Japan
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Hamarneh SR, Murphy CA, Shih CW, Frontera W, Torriani M, Irazoqui JE, Makimura H. Relationship between serum IGF-1 and skeletal muscle IGF-1 mRNA expression to phosphocreatine recovery after exercise in obese men with reduced GH. J Clin Endocrinol Metab 2015; 100:617-25. [PMID: 25375982 PMCID: PMC4318910 DOI: 10.1210/jc.2014-2711] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/19/2014] [Accepted: 10/30/2014] [Indexed: 02/06/2023]
Abstract
CONTEXT GH and IGF-1 are believed to be physiological regulators of skeletal muscle mitochondria. OBJECTIVE The objective of this study was to examine the relationship between GH/IGF-1 and skeletal muscle mitochondria in obese subjects with reduced GH secretion in more detail. DESIGN Fifteen abdominally obese men with reduced GH secretion were treated for 12 weeks with recombinant human GH. Subjects underwent (31)P-magnetic resonance spectroscopy to assess phosphocreatine (PCr) recovery as an in vivo measure of skeletal muscle mitochondrial function and percutaneous muscle biopsies to assess mRNA expression of IGF-1 and mitochondrial-related genes at baseline and 12 weeks. RESULTS At baseline, skeletal muscle IGF-1 mRNA expression was significantly associated with PCr recovery (r = 0.79; P = .01) and nuclear respiratory factor-1 (r = 0.87; P = .001), mitochondrial transcription factor A (r = 0.86; P = .001), peroxisome proliferator-activated receptor (PPAR)γ (r = 0.72; P = .02), and PPARα (r = 0.75; P = .01) mRNA expression, and trended to an association with PPARγ coactivator 1-α (r = 0.59; P = .07) mRNA expression. However, serum IGF-1 concentration was not associated with PCr recovery or any mitochondrial gene expression (all P > .10). Administration of recombinant human GH increased both serum IGF-1 (change, 218 ± 29 μg/L; P < .0001) and IGF-1 mRNA in muscle (fold change, 2.1 ± 0.3; P = .002). Increases in serum IGF-1 were associated with improvements in total body fat (r = -0.53; P = .04), trunk fat (r = -0.55; P = .03), and lean mass (r = 0.58; P = .02), but not with PCr recovery (P > .10). Conversely, increase in muscle IGF-1 mRNA was associated with improvements in PCr recovery (r = 0.74; P = .02), but not with body composition parameters (P > .10). CONCLUSION These data demonstrate a novel association of skeletal muscle mitochondria with muscle IGF-1 mRNA expression, but independent of serum IGF-1 concentrations.
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Affiliation(s)
- Sulaiman R Hamarneh
- Department of Surgery (S.R.H.), Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114; Program in Nutritional Metabolism (C.A.M., C.W.S., H.M.), Massachusetts General Hospital, Boston, Massachusetts 02114; Harvard College (C.W.S.), Boston, Massachusetts 02138; Department of Physical Medicine and Rehabilitation (W.F.), Vanderbilt University Medical Center, Nashville, Tennessee 37212; Department of Physical Medicine and Rehabilitation (W.F.), Harvard Medical School/Spaulding Rehabilitation Hospital, Boston, Massachusetts 02114; Department of Physiology (W.F.), University of Puerto Rico School of Medicine, San Juan, Puerto Rico 00936; and Department of Radiology (M.T.), Laboratory of Comparative Immunology, Center for the Study of Inflammatory Bowel Disease (J.E.I.), and Neuroendocrine Unit (H.M.), Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114
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Brunn J, Wiroth V, Kowalski M, Runge U, Sabolek M. Valproic acid in normal therapeutic concentration has no neuroprotective or differentiation influencing effects on long term expanded murine neural stem cells. Epilepsy Res 2014; 108:623-33. [DOI: 10.1016/j.eplepsyres.2014.02.005] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2013] [Revised: 01/31/2014] [Accepted: 02/08/2014] [Indexed: 01/15/2023]
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Physical exercise-induced adult neurogenesis: a good strategy to prevent cognitive decline in neurodegenerative diseases? BIOMED RESEARCH INTERNATIONAL 2014; 2014:403120. [PMID: 24818140 PMCID: PMC4000963 DOI: 10.1155/2014/403120] [Citation(s) in RCA: 73] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/14/2013] [Revised: 02/16/2014] [Accepted: 02/16/2014] [Indexed: 01/19/2023]
Abstract
Cumulative evidence has indicated that there is an important role for adult hippocampal neurogenesis in cognitive function. With the increasing prevalence of cognitive decline associated with neurodegenerative diseases among the ageing population, physical exercise, a potent enhancer of adult hippocampal neurogenesis, has emerged as a potential preventative strategy/treatment to reduce cognitive decline. Here we review the functional role of adult hippocampal neurogenesis in learning and memory, and how this form of structural plasticity is altered in neurodegenerative diseases known to involve cognitive impairment. We further discuss how physical exercise may contribute to cognitive improvement in the ageing brain by preserving adult neurogenesis, and review the recent approaches for measuring changes in neurogenesis in the live human brain.
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Xu E, Schwab M, Marette A. Role of protein tyrosine phosphatases in the modulation of insulin signaling and their implication in the pathogenesis of obesity-linked insulin resistance. Rev Endocr Metab Disord 2014; 15:79-97. [PMID: 24264858 DOI: 10.1007/s11154-013-9282-4] [Citation(s) in RCA: 51] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Insulin resistance is a major disorder that links obesity to type 2 diabetes mellitus (T2D). It involves defects in the insulin actions owing to a reduced ability of insulin to trigger key signaling pathways in major metabolic tissues. The pathogenesis of insulin resistance involves several inhibitory molecules that interfere with the tyrosine phosphorylation of the insulin receptor and its downstream effectors. Among those, growing interest has been developed toward the protein tyrosine phosphatases (PTPs), a large family of enzymes that can inactivate crucial signaling effectors in the insulin signaling cascade by dephosphorylating their tyrosine residues. Herein we briefly review the role of several PTPs that have been shown to be implicated in the regulation of insulin action, and then focus on the Src homology 2 (SH2) domain-containing SHP1 and SHP2 enzymes, since recent reports have indicated major roles for these PTPs in the control of insulin action and glucose metabolism. Finally, the therapeutic potential of targeting PTPs for combating insulin resistance and alleviating T2D will be discussed.
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Affiliation(s)
- Elaine Xu
- Department of Medicine, Cardiology Axis of the Institut Universitaire de Cardiologie et de Pneumologie de Québec (Hôpital Laval), Ste-Foy, Québec, Canada, G1V 4G2
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Jin S, Chen S, Li H, Lu Y, Xu G, Yang N. Associations of polymorphisms in GHRL, GHSR, and IGF1R genes with feed efficiency in chickens. Mol Biol Rep 2014; 41:3973-9. [PMID: 24566683 DOI: 10.1007/s11033-014-3265-8] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2013] [Accepted: 02/12/2014] [Indexed: 01/03/2023]
Abstract
The ghrelin (GHRL), ghrelin receptor (GHSR), and insulin-like growth factor 1 receptor (IGF1R) genes have crucial effects on body weight (BW), body weight gain (BWG), feed intake (FI), and feed conversion ratio (FCR) in many species. However, few studies on associations of GHRL, GHSR, and IGF1R with BWG, FI, and FCR have been reported in chickens. In this study, 16 SNPs in GHRL, GHSR, and IGF1R genes were genotyped by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS). The objective of this study was to examine the associations of GHRL, GHSR, and IGF1R genes polymorphisms with BW at 49 days (BW49) and 70 days (BW70) of age, BWG, FI, and FCR in the interval in two yellow meat-type populations with a total of 724 birds. The results showed that rs15675067 of GHRL was significantly associated with BW70, BWG, and FCR (P < 0.05). For GHSR, rs16675844 had significant effects on FI and FCR (P < 0.01), and that rs14678932 showed significant association with BWG and FI (P < 0.05). Rs14011780 of IGF1R was strongly associated with BW49, BW70, and FCR (P < 0.05). Furthermore, haplotypes based on three SNPs of rs14986828, rs15675067, and rs15675065 in GHRL were significantly associated with BW70 and FCR (P < 0.05). Meanwhile, a three-SNP haplotype comprising rs14011783, rs14011780, and rs14011776 in IGF1R showed significant effects on BW49, BW70, and FCR (P < 0.05). Therefore, it was concluded that the identified SNPs and analyzed haplotypes in this study might be useful for broiler breeding programs.
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Affiliation(s)
- Sihua Jin
- National Engineering Laboratory for Animal Breeding and MOA Key Laboratory of Animal Genetics and Breeding, Department of Animal Genetics and Breeding, College of Animal Science and Technology, China Agricultural University, Beijing, 100193, China
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Alemán JO, Eusebi LH, Ricciardiello L, Patidar K, Sanyal AJ, Holt PR. Mechanisms of obesity-induced gastrointestinal neoplasia. Gastroenterology 2014; 146:357-373. [PMID: 24315827 PMCID: PMC3978703 DOI: 10.1053/j.gastro.2013.11.051] [Citation(s) in RCA: 148] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/12/2013] [Revised: 10/30/2013] [Accepted: 11/14/2013] [Indexed: 02/06/2023]
Abstract
Obesity is among the fastest growing diseases worldwide; treatment is inadequate, and associated disorders, including gastrointestinal cancers, have high morbidity and mortality. An increased understanding of the mechanisms of obesity-induced carcinogenesis is required to develop methods to prevent or treat these cancers. In this report, we review the mechanisms of obesity-associated colorectal, esophageal, gastric, and pancreatic cancers and potential treatment strategies.
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Affiliation(s)
| | - Leonardo H. Eusebi
- Department of Medical and Surgical Sciences, University of Bologna, Italy
| | - Luigi Ricciardiello
- Department of Medical and Surgical Sciences, and Center for Applied Biomedical Research (CRBA), University of Bologna, Italy
| | - Kavish Patidar
- Virginia Commonwealth University School of Medicine, Richmond, VA, USA
| | - Arun J. Sanyal
- Virginia Commonwealth University School of Medicine, Richmond, VA, USA
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Sadagurski M, White MF. Integrating metabolism and longevity through insulin and IGF1 signaling. Endocrinol Metab Clin North Am 2013; 42:127-48. [PMID: 23391244 PMCID: PMC3982789 DOI: 10.1016/j.ecl.2012.11.008] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
The insulin pathway coordinates growth, development, metabolic homoeostasis, fertility, and stress resistance, which influence life span. Compensatory hyperinsulinemia to overcome systemic insulin resistance circumvents the immediate consequences of hyperglycemia. Work on flies, nematodes, and mice indicate that excess insulin signaling damages cellular function and accelerates aging. Maintenance of the central nervous system (CNS) has particular importance for life span. Reduced insulin/IGF1 signaling in the CNS can dysregulate peripheral energy homeostasis and metabolism, promote obesity, and extend life span. Genetic manipulations of insulin/IGF1 signaling components are revealing neuronal circuits that might resolve the central regulation of systemic metabolism from organism longevity.
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Affiliation(s)
- Marianna Sadagurski
- Department of Endocrinology, Children's Hospital Boston, Howard Hughes Medical Institute, Boston, MA 02115, USA
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Huang CW, Li YH, Hu SY, Chi JR, Lin GH, Lin CC, Gong HY, Chen JY, Chen RH, Chang SJ, Liu FG, Wu JL. Differential expression patterns of growth-related microRNAs in the skeletal muscle of Nile tilapia (Oreochromis niloticus)1. J Anim Sci 2012; 90:4266-79. [DOI: 10.2527/jas.2012-5142] [Citation(s) in RCA: 69] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
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Reindl KM, Sheridan MA. Peripheral regulation of the growth hormone-insulin-like growth factor system in fish and other vertebrates. Comp Biochem Physiol A Mol Integr Physiol 2012; 163:231-45. [DOI: 10.1016/j.cbpa.2012.08.003] [Citation(s) in RCA: 169] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2012] [Revised: 08/03/2012] [Accepted: 08/07/2012] [Indexed: 10/28/2022]
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Zhong H, Zhou Y, Liu S, Tao M, Long Y, Liu Z, Zhang C, Duan W, Hu J, Song C, Liu Y. Elevated expressions of GH/IGF axis genes in triploid crucian carp. Gen Comp Endocrinol 2012; 178:291-300. [PMID: 22713693 DOI: 10.1016/j.ygcen.2012.06.006] [Citation(s) in RCA: 43] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/31/2012] [Revised: 05/11/2012] [Accepted: 06/04/2012] [Indexed: 10/28/2022]
Abstract
Growth hormone (GH), growth hormone receptor (GHR) and insulin-like growth factor 1 (IGF-1) are pivotal signaling factors of the GH/IGF axis, which plays a crucial role in regulating growth in vertebrates. In this study, GH, GHR and IGF-1 cDNAs were cloned from triploid and tetraploid crucian carp. In addition, mRNA expression levels were characterized in diploid red crucian carp, triploids and tetraploids. Reverse transcriptase PCR indicated that GH genes were only expressed in the pituitary, while GHR and IGF-1 were widely expressed in all tested tissues. Real-time PCR study of different seasonal profiles showed that triploids had significantly higher expression of the studied genes during both the prespawning and the spawning season. Although different temperatures (22, 26 and 30°C) showed no significant effects on GH, GHR and IGF-1 mRNA expression in either diploids or triploids, triploids had higher expression levels than diploids at each temperature. After 1 week of fasting, the expression of all studied genes was reduced in both diploids and triploids, while the expressions levels were higher in triploids than in diploids. These results suggest that the elevated expression of GH/IGF axis genes in triploids plays a crucial role in the faster growth rate of triploids.
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Affiliation(s)
- Huan Zhong
- Key Laboratory of Protein Chemistry and Fish Developmental Biology of the Education Ministry of China, College of Life Sciences, Hunan Normal University, Changsha 410081, China
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Leal ADC, Canton APM, Montenegro LR, Coutinho DC, Arnhold IJP, Jorge AADL. [Mutations in insulin-like growth factor receptor 1 gene (IGF1R) resulting in intrauterine and postnatal growth retardation]. ACTA ACUST UNITED AC 2012; 55:541-9. [PMID: 22218435 DOI: 10.1590/s0004-27302011000800007] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2011] [Accepted: 10/20/2011] [Indexed: 11/22/2022]
Abstract
Approximately 10% of children born small-for-gestational age (SGA) do not show spontaneous growth catch-up. The causes of this deficit in prenatal growth and its maintenance after birth are not completely known, in most cases. Over the past eight years, several heterozygous inactivating mutations and deletions in IGF1R gene have been reported, indicating the role of defects in the IGFs/IGF1R axis as a cause of growth deficit. It has been hypothesized that at least 2.5% of children born SGA may have IGF1R gene defects. The clinical presentation of these patients is highly variable in the severity of growth retardation and hormonal parameters. In the most evident cases, patients have microcephaly, mild cognitive impairment and high levels of IGF-1, associated with short stature of prenatal onset. This review will describe the clinical, molecular and treatment of short stature with hrGH of children with mutations in the IGF1R gene.
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Affiliation(s)
- Andréa de Castro Leal
- Unidade de Endocrinologia do Desenvolvimento, Laboratório de Hormônios e Genética Molecular, Hospital das Clínicas, São Paulo, Brasil
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Protection of blood retinal barrier and systemic vasculature by insulin-like growth factor binding protein-3. PLoS One 2012; 7:e39398. [PMID: 22792172 PMCID: PMC3391198 DOI: 10.1371/journal.pone.0039398] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2011] [Accepted: 05/22/2012] [Indexed: 11/19/2022] Open
Abstract
Previously, we showed that insulin growth factor (IGF)-1 binding protein-3 (IGFBP-3), independent of IGF-1, reduces pathological angiogenesis in a mouse model of the oxygen-induced retinopathy (OIR). The current study evaluates novel endothelium-dependent functions of IGFBP-3 including blood retinal barrier (BRB) integrity and vasorelaxation. To evaluate vascular barrier function, either plasmid expressing IGFBP-3 under the regulation of an endothelial-specific promoter or a control plasmid was injected into the vitreous humor of mouse pups (P1) and compared to the non-injected eyes of the same pups undergoing standard OIR protocol. Prior to sacrifice, the mice were given an injection of horseradish peroxidase (HRP). IGFBP-3 plasmid-injected eyes displayed near-normal vessel morphology and enhanced vascular barrier function. Further, in vitro IGFBP-3 protects retinal endothelial cells from VEGF-induced loss of junctional integrity by antagonizing the dissociation of the junctional complexes. To assess the vasodilatory effects of IGFBP-3, rat posterior cerebral arteries were examined in vitro. Intraluminal IGFBP-3 decreased both pressure- and serotonin-induced constrictions by stimulating nitric oxide (NO) release that were blocked by L-NAME or scavenger receptor-B1 neutralizing antibody (SRB1-Ab). Both wild-type and IGF-1-nonbinding mutant IGFBP-3 (IGFBP-3NB) stimulated eNOS activity/NO release to a similar extent in human microvascular endothelial cells (HMVECs). NO release was neither associated with an increase in intracellular calcium nor decreased by Ca2+/calmodulin-dependent protein kinase II (CamKII) blockade; however, dephosphorylation of eNOS-Thr495 was observed. Phosphatidylinositol 3-kinase (PI3K) activity and Akt-Ser473 phosphorylation were both increased by IGFBP-3 and selectively blocked by the SRB1-Ab or PI3K blocker LY294002. In conclusion, IGFBP-3 mediates protective effects on BRB integrity and mediates robust NO release to stimulate vasorelaxation via activation of SRB1. This response is IGF-1- and calcium-independent, but requires PI3K/Akt activation, suggesting that IGFBP-3 has novel protective effects on retinal and systemic vasculature and may be a therapeutic candidate for ocular complications such as diabetic retinopathy.
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Siddle K. Molecular basis of signaling specificity of insulin and IGF receptors: neglected corners and recent advances. Front Endocrinol (Lausanne) 2012; 3:34. [PMID: 22649417 PMCID: PMC3355962 DOI: 10.3389/fendo.2012.00034] [Citation(s) in RCA: 111] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/15/2011] [Accepted: 02/13/2012] [Indexed: 12/15/2022] Open
Abstract
Insulin and insulin-like growth factor (IGF) receptors utilize common phosphoinositide 3-kinase/Akt and Ras/extracellular signal-regulated kinase signaling pathways to mediate a broad spectrum of "metabolic" and "mitogenic" responses. Specificity of insulin and IGF action in vivo must in part reflect expression of receptors and responsive pathways in different tissues but it is widely assumed that it is also determined by the ligand binding and signaling mechanisms of the receptors. This review focuses on receptor-proximal events in insulin/IGF signaling and examines their contribution to specificity of downstream responses. Insulin and IGF receptors may differ subtly in the efficiency with which they recruit their major substrates (IRS-1 and IRS-2 and Shc) and this could influence effectiveness of signaling to "metabolic" and "mitogenic" responses. Other substrates (Grb2-associated binder, downstream of kinases, SH2Bs, Crk), scaffolds (RACK1, β-arrestins, cytohesins), and pathways (non-receptor tyrosine kinases, phosphoinositide kinases, reactive oxygen species) have been less widely studied. Some of these components appear to be specifically involved in "metabolic" or "mitogenic" signaling but it has not been shown that this reflects receptor-preferential interaction. Very few receptor-specific interactions have been characterized, and their roles in signaling are unclear. Signaling specificity might also be imparted by differences in intracellular trafficking or feedback regulation of receptors, but few studies have directly addressed this possibility. Although published data are not wholly conclusive, no evidence has yet emerged for signaling mechanisms that are specifically engaged by insulin receptors but not IGF receptors or vice versa, and there is only limited evidence for differential activation of signaling mechanisms that are common to both receptors. Cellular context, rather than intrinsic receptor activity, therefore appears to be the major determinant of whether responses to insulin and IGFs are perceived as "metabolic" or "mitogenic."
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Affiliation(s)
- Kenneth Siddle
- University of Cambridge Metabolic Research Laboratories and Department of Clinical Biochemistry, Institute of Metabolic Science, Addenbrooke's Hospital Cambridge, UK.
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Sun CF, Tao Y, Jiang XY, Zou SM. IGF binding protein 1 is correlated with hypoxia-induced growth reduce and developmental defects in grass carp (Ctenopharyngodon idellus) embryos. Gen Comp Endocrinol 2011; 172:409-15. [PMID: 21501614 DOI: 10.1016/j.ygcen.2011.04.005] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/05/2011] [Revised: 03/22/2011] [Accepted: 04/04/2011] [Indexed: 10/18/2022]
Abstract
The effects of hypoxia on embryonic development and the underlying cellular and molecular mechanisms are poorly understood in teleost fish, although the hypoxic effects on embryonic growth and development have been reported in the zebrafish model. Here, we found that hypoxia caused significant developmental delay and growth retardation during grass carp embryogenesis. Placing the embryos in hypoxic conditions at different developmental stages strongly induced the mRNA expression of insulin-like growth factor-binding protein 1 (IGFBP1), an inhibitory protein that binds to IGF and inhibits its subsequent actions in vivo. Further gain-of-function analysis results provided strong evidence to support the hypothesis that IGFBP1 plays an important role in mediating hypoxic-induced growth and developmental defects. Overexpression of IGFBP1 mRNA reduced the growth rate to a degree that was similar to hypoxia. Additionally, overexpression of IGFBP1 caused significant developmental defects in the formation of midline, somite and hindbrain structures during grass carp embryogenesis. Taken together, our studies suggest that IGFBP1 plays a key role in mediating these hypoxia-induced embryonic growth retardation and developmental delay in grass carp.
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Affiliation(s)
- Cheng-Fei Sun
- Key Laboratory of Aquatic Genetic Resources and Utilization, Shanghai Ocean University, Shanghai, China
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