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Lesley A Hill Departments of Cellular and Physiological Sciences and Obstetrics and Gynaecology, The University of British Columbia, Vancouver, British Columbia, Canada

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Dimitra A Vassiliadi Endocrine Unit, Second Department of Internal Medicine-Research Institute and Diabetes Center, Attiko University Hospital, Athens, Greece

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Ioanna Dimopoulou Endocrine Unit, Second Department of Internal Medicine-Research Institute and Diabetes Center, Attiko University Hospital, Athens, Greece

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Anna J Anderson BHF Centre for Cardiovascular Science, Queen’s Medical Research Institute, University of Edinburgh, Edinburgh, United Kingdom

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Luke D Boyle BHF Centre for Cardiovascular Science, Queen’s Medical Research Institute, University of Edinburgh, Edinburgh, United Kingdom

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Alixe H M Kilgour BHF Centre for Cardiovascular Science, Queen’s Medical Research Institute, University of Edinburgh, Edinburgh, United Kingdom

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Roland H Stimson BHF Centre for Cardiovascular Science, Queen’s Medical Research Institute, University of Edinburgh, Edinburgh, United Kingdom

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Yoan Machado Department of Biochemistry and Molecular Biology, The University of British Columbia, Vancouver, British Columbia, Canada

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Christopher M Overall Department of Biochemistry and Molecular Biology, The University of British Columbia, Vancouver, British Columbia, Canada

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Brian R Walker BHF Centre for Cardiovascular Science, Queen’s Medical Research Institute, University of Edinburgh, Edinburgh, United Kingdom
Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, United Kingdom

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John G Lewis Canterbury Health Laboratories, Christchurch, New Zealand

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Geoffrey L Hammond Departments of Cellular and Physiological Sciences and Obstetrics and Gynaecology, The University of British Columbia, Vancouver, British Columbia, Canada

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Corticosteroid-binding globulin (CBG) transports glucocorticoids in blood and is a serine protease inhibitor family member. Human CBG has a reactive center loop (RCL) which, when cleaved by neutrophil elastase (NE), disrupts its steroid-binding activity. Measurements of CBG levels are typically based on steroid-binding capacity or immunoassays. Discrepancies in ELISAs using monoclonal antibodies that discriminate between intact vs RCL-cleaved CBG have been interpreted as evidence that CBG with a cleaved RCL and low affinity for cortisol exists in the circulation. We examined the biochemical properties of plasma CBG in samples with discordant ELISA measurements and sought to identify RCL-cleaved CBG in human blood samples. Plasma CBG-binding capacity and ELISA values were consistent in arterial and venous blood draining skeletal muscle, liver and brain, as well as from a tissue (adipose) expected to contain activated neutrophils in obese individuals. Moreover, RCL-cleaved CBG was undetectable in plasma from critically ill patients, irrespective of whether their ELISA measurements were concordant or discordant. We found no evidence of RCL-cleaved CBG in plasma using a heat-dependent polymerization assay, and CBG that resists immunoprecipitation with a monoclonal antibody designed to specifically recognize an intact RCL, bound steroids with a high affinity. In addition, mass spectrometry confirmed the absence of NE-cleaved CBG in plasma in which ELISA values were highly discordant. Human CBG with a NE-cleaved RCL and low affinity for steroids is absent in blood samples, and CBG ELISA discrepancies likely reflect structural differences that alter epitopes recognized by specific monoclonal antibodies.

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Vikte Lionikaite Centre for Bone and Arthritis Research, Department of Internal Medicine and Clinical Nutrition, Institute for Medicine, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden

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Karin L Gustafsson Centre for Bone and Arthritis Research, Department of Internal Medicine and Clinical Nutrition, Institute for Medicine, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden

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Anna Westerlund Centre for Bone and Arthritis Research, Department of Internal Medicine and Clinical Nutrition, Institute for Medicine, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden

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Sara H Windahl Centre for Bone and Arthritis Research, Department of Internal Medicine and Clinical Nutrition, Institute for Medicine, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden

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Antti Koskela Department of Anatomy and Cell Biology, Medical Research Center, University of Oulu, Oulu, Finland

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Juha Tuukkanen Department of Anatomy and Cell Biology, Medical Research Center, University of Oulu, Oulu, Finland

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Helena Johansson Institute for Health and Aging, Catholic University of Australia, Melbourne, Australia

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Claes Ohlsson Centre for Bone and Arthritis Research, Department of Internal Medicine and Clinical Nutrition, Institute for Medicine, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden

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H Herschel Conaway Department of Physiology and Biophysics, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA

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Petra Henning Centre for Bone and Arthritis Research, Department of Internal Medicine and Clinical Nutrition, Institute for Medicine, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden

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Ulf H Lerner Centre for Bone and Arthritis Research, Department of Internal Medicine and Clinical Nutrition, Institute for Medicine, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden

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Excess vitamin A has been associated with decreased cortical bone thickness and increased fracture risk. While most studies in rodents have employed high dosages of vitamin A for short periods of time, we investigated the bone phenotype in mice after longer exposure to more clinically relevant doses. For 1, 4 and 10 weeks, mice were fed a control diet (4.5 µg retinyl acetate/g chow), a diet modeled from the human upper tolerable limit (UTL; 20 µg retinyl acetate/g chow) and a diet three times UTL (supplemented; 60 µg retinyl acetate/g chow). Time-dependent decreases in periosteal circumference and bone mineral content were noted with the supplemented dose. These reductions in cortical bone resulted in a significant time-dependent decrease of predicted strength and a non-significant trend toward reduced bone strength as analyzed by three-point bending. Trabecular bone in tibiae and vertebrae remained unaffected when vitamin A was increased in the diet. Dynamic histomorphometry demonstrated that bone formation was substantially decreased after 1 week of treatment at the periosteal site with the supplemental dose. Increasing amount of vitamin A decreased endocortical circumference, resulting in decreased marrow area, a response associated with enhanced endocortical bone formation. In the presence of bisphosphonate, vitamin A had no effect on cortical bone, suggesting that osteoclasts are important, even if effects on bone resorption were not detected by osteoclast counting, genes in cortical bone or analysis of serum TRAP5b and CTX. In conclusion, our results indicate that even clinically relevant doses of vitamin A have a negative impact on the amount of cortical bone.

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Jin-Ran Chen Arkansas Children’s Nutrition Center, Little Rock, Arkansas, USA
Department of Pediatrics, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA

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Oxana P Lazarenko Arkansas Children’s Nutrition Center, Little Rock, Arkansas, USA
Department of Pediatrics, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA

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Haijun Zhao Arkansas Children’s Nutrition Center, Little Rock, Arkansas, USA
Department of Pediatrics, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA

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Alexander W Alund Interdisciplinary Biomedical Sciences , University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA

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Kartik Shankar Arkansas Children’s Nutrition Center, Little Rock, Arkansas, USA
Department of Pediatrics, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA

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Intrauterine or early postnatal high-fat diet (HFD) has substantial influences on adult offspring health; however, studies of HFD-induced maternal obesity on regulation of adult offspring bone formation are sparse. Here, we investigated the effects of HFD-induced maternal obesity on both fetal and adult offspring skeletal development. We found that HFD-induced maternal obesity significantly decreased fetal skeletal development, but enhanced fetal osteoblastic cell senescence signaling and significantly increased the expression of inflammatory factors of the senescence-associated secretory phenotype (SASP) in osteo-progenitors. It was found that p300/CBP activation led to H3K27 acetylation to increase the expression of senescence-related genes and PPARγ in embryonic mouse osteogenic calvarial cells from HFD obese dams. These results were recapitulated in human umbilical cord mesenchymal stem cells (UC MSCs) isolated from offspring of pregnant obese and lean mothers following delivery. Regardless of postnatal HFD challenge, adult offspring from HFD obese dams showed significantly suppressed bone formation. Such early involution of bone formation of adult offspring from HFD obese dams may at least in part due to histone acetylation, i.e., epigenetic regulation of genes involved in cell senescence signaling in pre-osteoblasts from prenatal development. These findings indicate fetal pre-osteoblastic cell senescence signaling is epigenetically regulated by maternal obesity to repress bone formation in adult offspring in rodents and suggest that at least some of these effects may also manifest in humans.

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Ismael González-García Department of Physiology, CiMUS, University of Santiago de Compostela-Instituto de Investigación Sanitaria, Santiago de Compostela, Spain
CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), Santiago de Compostela, Spain

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Pablo B Martínez de Morentin Department of Physiology, CiMUS, University of Santiago de Compostela-Instituto de Investigación Sanitaria, Santiago de Compostela, Spain
CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), Santiago de Compostela, Spain

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Ánxela Estévez-Salguero Department of Physiology, CiMUS, University of Santiago de Compostela-Instituto de Investigación Sanitaria, Santiago de Compostela, Spain
CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), Santiago de Compostela, Spain

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Cristina Contreras Department of Physiology, CiMUS, University of Santiago de Compostela-Instituto de Investigación Sanitaria, Santiago de Compostela, Spain
CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), Santiago de Compostela, Spain

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Amparo Romero-Picó Department of Physiology, CiMUS, University of Santiago de Compostela-Instituto de Investigación Sanitaria, Santiago de Compostela, Spain
CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), Santiago de Compostela, Spain

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Johan Fernø Hormone Laboratory, Haukeland University Hospital, Bergen, Norway
KG Jebsen Center for Diabetes Research, Department of Clinical Science, University of Bergen, Bergen, Norway

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Rubén Nogueiras Department of Physiology, CiMUS, University of Santiago de Compostela-Instituto de Investigación Sanitaria, Santiago de Compostela, Spain
CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), Santiago de Compostela, Spain

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Carlos Diéguez Department of Physiology, CiMUS, University of Santiago de Compostela-Instituto de Investigación Sanitaria, Santiago de Compostela, Spain
CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), Santiago de Compostela, Spain

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Manuel Tena-Sempere Department of Cell Biology, Physiology and Immunology, University of Córdoba, Córdoba, Spain
Instituto Maimónides de Investigación Biomédica (IMIBIC)/Hospital Reina Sofía, Córdoba, Spain
FiDiPro Program, University of Turku, Turku, Finland

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Sulay Tovar Department of Physiology, CiMUS, University of Santiago de Compostela-Instituto de Investigación Sanitaria, Santiago de Compostela, Spain
CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), Santiago de Compostela, Spain

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Miguel López Department of Physiology, CiMUS, University of Santiago de Compostela-Instituto de Investigación Sanitaria, Santiago de Compostela, Spain
CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), Santiago de Compostela, Spain

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Current evidence suggests that estradiol (E2), the main ovarian steroid, modulates energy balance by regulating both feeding and energy expenditure at the central level, through the energy sensor AMP-activated protein kinase (AMPK). We hypothesized that the hypothalamic mechanistic target of rapamycin (mTOR) pathway, a well-established nutrient sensor and modulator of appetite and puberty, could also mediate the anorectic effect of E2. Our data showed that ovariectomy (OVX) elicited a marked downregulation of the mTOR signaling in the arcuate nucleus of the hypothalamus (ARC), an effect that was reversed by either E2 replacement or central estrogen receptor alpha (ERα) agonism. The significance of this molecular signaling was given by the genetic inactivation of S6 kinase B1 (S6K1, a key downstream mTOR effector) in the ARC, which prevented the E2-induced hypophagia and weight loss. Overall, these data indicate that E2 induces hypophagia through modulation of mTOR pathway in the ARC.

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Sara Della Torre Center of Excellence on Neurodegenerative Diseases, University of Milan, Milan, Italy
Department of Pharmacological and Biomolecular Sciences, University of Milan, Milan, Italy

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Gianpaolo Rando Center of Excellence on Neurodegenerative Diseases, University of Milan, Milan, Italy
Department of Pharmacological and Biomolecular Sciences, University of Milan, Milan, Italy

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Clara Meda Center of Excellence on Neurodegenerative Diseases, University of Milan, Milan, Italy
Department of Pharmacological and Biomolecular Sciences, University of Milan, Milan, Italy

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Paolo Ciana Department of Oncology and Hemato-Oncology, University of Milan, Milan, Italy

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Luisa Ottobrini Department of Pathophysiology and Transplantation, University of Milan, Milan, Italy

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Adriana Maggi Center of Excellence on Neurodegenerative Diseases, University of Milan, Milan, Italy
Department of Pharmacological and Biomolecular Sciences, University of Milan, Milan, Italy

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Oestrogens are well-known proliferation and differentiation factors that play an essential role in the correct development of sex-related organs and behaviour in mammals. With the use of the ERE-Luc reporter mouse model, we show herein that throughout mouse development, oestrogen receptors (ERs) are active starting from day 12 post conception. Most interestingly, we show that prenatal luciferase expression in each organ is proportionally different in relation to the germ layer of the origin. The luciferase content is highest in ectoderm-derived organs (such as brain and skin) and is lowest in endoderm-derived organs (such as liver, lung, thymus and intestine). Consistent with the testosterone surge occurring in male mice at the end of pregnancy, in the first 2 days after birth, we observed a significant increase in the luciferase content in several organs, including the liver, bone, gonads and hindbrain. The results of the present study show a widespread transcriptional activity of ERs in developing embryos, pointing to the potential contribution of these receptors in the development of non-reproductive as well as reproductive organs. Consequently, the findings reported here might be relevant in explaining the significant differences in male and female physiopathology reported by a growing number of studies and may underline the necessity for more systematic analyses aimed at the identification of the prenatal effects of drugs interfering with ER signalling, such as aromatase inhibitors or endocrine disrupter chemicals.

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S J Brandt Institute for Diabetes and Obesity, Helmholtz Diabetes Center, Helmholtz Zentrum München, German Research Center for Environmental Health (GmbH), Neuherberg, Germany
German Center for Diabetes Research (DZD), Neuherberg, Germany

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M Kleinert Institute for Diabetes and Obesity, Helmholtz Diabetes Center, Helmholtz Zentrum München, German Research Center for Environmental Health (GmbH), Neuherberg, Germany
German Center for Diabetes Research (DZD), Neuherberg, Germany

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M H Tschöp Institute for Diabetes and Obesity, Helmholtz Diabetes Center, Helmholtz Zentrum München, German Research Center for Environmental Health (GmbH), Neuherberg, Germany
German Center for Diabetes Research (DZD), Neuherberg, Germany
Division of Metabolic Diseases, Technische Universität, Munich, Germany

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T D Müller Institute for Diabetes and Obesity, Helmholtz Diabetes Center, Helmholtz Zentrum München, German Research Center for Environmental Health (GmbH), Neuherberg, Germany
German Center for Diabetes Research (DZD), Neuherberg, Germany

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Obesity is a worldwide pandemic, which can be fatal for the most extremely affected individuals. Lifestyle interventions such as diet and exercise are largely ineffective and current anti-obesity medications offer little in the way of significant or sustained weight loss. Bariatric surgery is effective, but largely restricted to only a small subset of extremely obese patients. While the hormonal factors mediating sustained weight loss and remission of diabetes by bariatric surgery remain elusive, a new class of polypharmacological drugs shows potential to shrink the gap in efficacy between a surgery and pharmacology. In essence, this new class of drugs combines the beneficial effects of several independent hormones into a single entity, thereby combining their metabolic efficacy to improve systems metabolism. Such unimolecular drugs include single molecules with agonism at the receptors for glucagon, glucagon-like peptide 1 and the glucose-dependent insulinotropic polypeptide. In preclinical studies, these specially tailored multiagonists outperform both their mono-agonist components and current best in class anti-obesity medications. While clinical trials and vigorous safety analyses are ongoing, these drugs are poised to have a transformative effect in anti-obesity therapy and might hopefully lead the way to a new era in weight-loss pharmacology.

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Gisela Helfer School of Chemistry and Biosciences, University of Bradford, Bradford, UK

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Qing-Feng Wu State Key Laboratory of Molecular Development Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing, China

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Metabolic syndrome is a global public health problem and predisposes individuals to obesity, diabetes and cardiovascular disease. Although the underlying mechanisms remain to be elucidated, accumulating evidence has uncovered a critical role of adipokines. Chemerin, encoded by the gene Rarres2, is a newly discovered adipokine involved in inflammation, adipogenesis, angiogenesis and energy metabolism. In humans, local and circulating levels of chemerin are positively correlated with BMI and obesity-related biomarkers. In this review, we discuss both peripheral and central roles of chemerin in regulating body metabolism. In general, chemerin is upregulated in obese and diabetic animals. Previous studies by gain or loss of function show an association of chemerin with adipogenesis, glucose homeostasis, food intake and body weight. In the brain, the hypothalamus integrates peripheral afferent signals including adipokines to regulate appetite and energy homeostasis. Chemerin increases food intake in seasonal animals by acting on hypothalamic stem cells, the tanycytes. In peripheral tissues, chemerin increases cell expansion, inflammation and angiogenesis in adipose tissue, collectively resulting in adiposity. While chemerin signalling enhances insulin secretion from pancreatic islets, contradictory results have been reported on how chemerin links to obesity and insulin resistance. Given the association of chemerin with obesity comorbidities in humans, advances in translational research targeting chemerin are expected to mitigate metabolic disorders. Together, the exciting findings gathered in the last decade clearly indicate a crucial multifaceted role for chemerin in the regulation of energy balance, making it a promising candidate for urgently needed pharmacological treatment strategies for obesity.

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K L Gustafsson Center for Bone and Arthritis Research, Department of Internal Medicine and Clinical Nutrition, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden

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K H Nilsson Center for Bone and Arthritis Research, Department of Internal Medicine and Clinical Nutrition, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden

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H H Farman Center for Bone and Arthritis Research, Department of Internal Medicine and Clinical Nutrition, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden

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A Andersson Center for Bone and Arthritis Research, Department of Rheumatology and Inflammation Research, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden

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V Lionikaite Center for Bone and Arthritis Research, Department of Internal Medicine and Clinical Nutrition, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden

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P Henning Center for Bone and Arthritis Research, Department of Internal Medicine and Clinical Nutrition, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden

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J Wu Center for Bone and Arthritis Research, Department of Internal Medicine and Clinical Nutrition, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden

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S H Windahl Center for Bone and Arthritis Research, Department of Internal Medicine and Clinical Nutrition, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden

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U Islander Center for Bone and Arthritis Research, Department of Rheumatology and Inflammation Research, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden

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S Movérare-Skrtic Center for Bone and Arthritis Research, Department of Internal Medicine and Clinical Nutrition, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden

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K Sjögren Center for Bone and Arthritis Research, Department of Internal Medicine and Clinical Nutrition, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden

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H Carlsten Center for Bone and Arthritis Research, Department of Rheumatology and Inflammation Research, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden

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J-Å Gustafsson Center for Nuclear Receptors and Cell Signaling, Department of Biology and Biochemistry, University of Houston, Houston, Texas, USA

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C Ohlsson Center for Bone and Arthritis Research, Department of Internal Medicine and Clinical Nutrition, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden

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M K Lagerquist Center for Bone and Arthritis Research, Department of Internal Medicine and Clinical Nutrition, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden

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Estrogen treatment has positive effects on the skeleton, and we have shown that estrogen receptor alpha (ERα) expression in cells of hematopoietic origin contributes to a normal estrogen treatment response in bone tissue. T lymphocytes are implicated in the estrogenic regulation of bone mass, but it is not known whether T lymphocytes are direct estrogen target cells. Therefore, the aim of this study was to determine the importance of ERα expression in T lymphocytes for the estrogenic regulation of the skeleton using female mice lacking ERα expression specifically in T lymphocytes (Lck-ERα−/−) and ERαflox/flox littermate (control) mice. Deletion of ERα expression in T lymphocytes did not affect bone mineral density (BMD) in sham-operated Lck-ERα−/− compared to control mice, and ovariectomy (ovx) resulted in a similar decrease in BMD in control and Lck-ERα−/− mice compared to sham-operated mice. Furthermore, estrogen treatment of ovx Lck-ERα−/− led to an increased BMD that was indistinguishable from the increase seen after estrogen treatment of ovx control mice. Detailed analysis of both the appendicular (femur) and axial (vertebrae) skeleton showed that both trabecular and cortical bone parameters responded to a similar extent regardless of the presence of ERα in T lymphocytes. In conclusion, ERα expression in T lymphocytes is dispensable for normal estrogenic regulation of bone mass in female mice.

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Thomas Funck-Brentano Centre for Bone and Arthritis Research, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden

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Karin H Nilsson Centre for Bone and Arthritis Research, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden

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Robert Brommage Centre for Bone and Arthritis Research, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden

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Petra Henning Centre for Bone and Arthritis Research, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden

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Ulf H Lerner Centre for Bone and Arthritis Research, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden

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Antti Koskela Unit of Cancer Research and Translational Medicine, MRC Oulu and Department of Anatomy and Cell Biology, University of Oulu, Oulu, Finland

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Juha Tuukkanen Unit of Cancer Research and Translational Medicine, MRC Oulu and Department of Anatomy and Cell Biology, University of Oulu, Oulu, Finland

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Martine Cohen-Solal BIOSCAR UMRS 1132, Université Paris Diderot, Sorbonne Paris Cité, INSERM, Paris, France

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Sofia Movérare-Skrtic Centre for Bone and Arthritis Research, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden

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Claes Ohlsson Centre for Bone and Arthritis Research, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden

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WNT signaling is involved in the tumorigenesis of various cancers and regulates bone homeostasis. Palmitoleoylation of WNTs by Porcupine is required for WNT activity. Porcupine inhibitors are under development for cancer therapy. As the possible side effects of Porcupine inhibitors on bone health are unknown, we determined their effects on bone mass and strength. Twelve-week-old C57BL/6N female mice were treated by the Porcupine inhibitors LGK974 (low dose = 3 mg/kg/day; high dose = 6 mg/kg/day) or Wnt-C59 (10 mg/kg/day) or vehicle for 3 weeks. Bone parameters were assessed by serum biomarkers, dual-energy X-ray absorptiometry, µCT and histomorphometry. Bone strength was measured by the 3-point bending test. The Porcupine inhibitors were well tolerated demonstrated by normal body weight. Both doses of LGK974 and Wnt-C59 reduced total body bone mineral density compared with vehicle treatment (P < 0.001). Cortical thickness of the femur shaft (P < 0.001) and trabecular bone volume fraction in the vertebral body (P < 0.001) were reduced by treatment with LGK974 or Wnt-C59. Porcupine inhibition reduced bone strength in the tibia (P < 0.05). The cortical bone loss was the result of impaired periosteal bone formation and increased endocortical bone resorption and the trabecular bone loss was caused by reduced trabecular bone formation and increased bone resorption. Porcupine inhibitors exert deleterious effects on bone mass and strength caused by a combination of reduced bone formation and increased bone resorption. We suggest that cancer targeted therapies using Porcupine inhibitors may increase the risk of fractures.

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Ashley Patton Department of Specialty Medicine, Heritage College of Osteopathic Medicine, Ohio University, Athens, Ohio, USA
Diabetes Institute, Ohio University, Athens, Ohio, USA
Department of Biological Sciences, Ohio University, Athens, Ohio, USA
Molecular & Cellular Biology Program, College of Arts and Sciences, Ohio University, Athens, Ohio, USA

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Tyler Church Department of Specialty Medicine, Heritage College of Osteopathic Medicine, Ohio University, Athens, Ohio, USA
Diabetes Institute, Ohio University, Athens, Ohio, USA

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Caroline Wilson Department of Chemical and Biomolecular Engineering, Russ College of Engineering and Technology, Ohio University, Athens, Ohio, USA

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Jean Thuma Department of Specialty Medicine, Heritage College of Osteopathic Medicine, Ohio University, Athens, Ohio, USA
Diabetes Institute, Ohio University, Athens, Ohio, USA

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Douglas J Goetz Department of Chemical and Biomolecular Engineering, Russ College of Engineering and Technology, Ohio University, Athens, Ohio, USA
Molecular & Cellular Biology Program, College of Arts and Sciences, Ohio University, Athens, Ohio, USA
Biomedical Engineering Program, Ohio University, Athens, Ohio, USA

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Darlene E Berryman Diabetes Institute, Ohio University, Athens, Ohio, USA
Department of Biomedical Sciences, Ohio University, Athens, Ohio, USA
The Edison Biotechnology Institute, Ohio University, Athens, Ohio, USA

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Edward O List Department of Specialty Medicine, Heritage College of Osteopathic Medicine, Ohio University, Athens, Ohio, USA
Diabetes Institute, Ohio University, Athens, Ohio, USA
The Edison Biotechnology Institute, Ohio University, Athens, Ohio, USA

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Frank Schwartz Department of Specialty Medicine, Heritage College of Osteopathic Medicine, Ohio University, Athens, Ohio, USA
Diabetes Institute, Ohio University, Athens, Ohio, USA

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Kelly D McCall Department of Specialty Medicine, Heritage College of Osteopathic Medicine, Ohio University, Athens, Ohio, USA
Diabetes Institute, Ohio University, Athens, Ohio, USA
Department of Biological Sciences, Ohio University, Athens, Ohio, USA
Molecular & Cellular Biology Program, College of Arts and Sciences, Ohio University, Athens, Ohio, USA
Biomedical Engineering Program, Ohio University, Athens, Ohio, USA
Department of Biomedical Sciences, Ohio University, Athens, Ohio, USA

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Nonalcoholic fatty liver disease (NAFLD) is the hepatic manifestation of both metabolic and inflammatory diseases and has become the leading chronic liver disease worldwide. High-fat (HF) diets promote an increased uptake and storage of free fatty acids (FFAs) and triglycerides (TGs) in hepatocytes, which initiates steatosis and induces lipotoxicity, inflammation and insulin resistance. Activation and signaling of Toll-like receptor 4 (TLR4) by FFAs induces inflammation evident in NAFLD and insulin resistance. Currently, there are no effective treatments to specifically target inflammation associated with this disease. We have established the efficacy of phenylmethimazole (C10) to prevent lipopolysaccharide and palmitate-induced TLR4 signaling. Because TLR4 is a key mediator in pro-inflammatory responses, it is a potential therapeutic target for NAFLD. Here, we show that treatment with C10 inhibits HF diet-induced inflammation in both liver and mesenteric adipose tissue measured by a decrease in mRNA levels of pro-inflammatory cytokines. Additionally, C10 treatment improves glucose tolerance and hepatic steatosis despite the development of obesity due to HF diet feeding. Administration of C10 after 16 weeks of HF diet feeding reversed glucose intolerance, hepatic inflammation, and improved hepatic steatosis. Thus, our findings establish C10 as a potential therapeutic for the treatment of NAFLD.

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