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Stuart A Morgan Institute of Metabolism & Systems Research, University of Birmingham, Birmingham, UK
Department of Biosciences, Nottingham Trent University, Nottingham, UK

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Laura L Gathercole Department of Biological & Medical Sciences, Oxford Brooks University, Oxford, UK

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Zaki K Hassan-Smith Institute of Metabolism & Systems Research, University of Birmingham, Birmingham, UK

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Jeremy Tomlinson Radcliffe Department of Medicine, University of Oxford, Oxford, UK

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Paul M Stewart Institute of Metabolism & Systems Research, University of Birmingham, Birmingham, UK
NEXUS, Discovery Way, University of Leeds, Leeds, UK

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Gareth G Lavery Institute of Metabolism & Systems Research, University of Birmingham, Birmingham, UK
Department of Biosciences, Nottingham Trent University, Nottingham, UK

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The aged phenotype shares several metabolic similarities with that of circulatory glucocorticoid excess (Cushing’s syndrome), including type 2 diabetes, obesity, hypertension, and myopathy. We hypothesise that local tissue generation of glucocorticoids by 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1), which converts 11-dehydrocorticosterone to active corticosterone in rodents (corticosterone to cortisol in man), plays a role in driving age-related chronic disease. In this study, we have examined the impact of ageing on glucocorticoid metabolism, insulin tolerance, adiposity, muscle strength, and blood pressure in both wildtype (WT) and transgenic male mice with a global deletion of 11β-HSD1 (11β-HSD1−/−) following 4 months high-fat feeding. We found that high fat-fed 11β-HSD1−/− mice were protected from age-related glucose intolerance and hyperinsulinemia when compared to age/diet-matched WTs. By contrast, aged 11β-HSD1−/− mice were not protected from the onset of sarcopenia observed in the aged WTs. Young 11β-HSD1−/− mice were partially protected from diet-induced obesity; however, this partial protection was lost with age. Despite greater overall obesity, the aged 11β-HSD1−/− animals stored fat in more metabolically safer adipose depots as compared to the aged WTs. Serum analysis revealed both WT and 11β-HSD1−/− mice had an age-related increase in morning corticosterone. Surprisingly, 11β-HSD1 oxo-reductase activity in the liver and skeletal muscle was unchanged with age in WT mice and decreased in gonadal adipose tissue. These data suggest that deletion of 11β-HSD1 in high fat-fed, but not chow-fed, male mice protects from age-related insulin resistance and supports a metabolically favourable fat distribution.

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Lara H Sattgast Skeletal Biology Laboratory, School of Biological and Population Health Sciences, Oregon State University, Corvallis, Oregon, USA

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Adam J Branscum Biostatistics Program, School of Biological and Population Health Sciences, Oregon State University, Corvallis, Oregon, USA

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Natali Newman Division of Neuroscience, Oregon National Primate Research Center, Oregon Health and Science University, Beaverton, Oregon, USA

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Steven W Gonzales Division of Neuroscience, Oregon National Primate Research Center, Oregon Health and Science University, Beaverton, Oregon, USA

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Mary Lauren Benton Department of Computer Science, Baylor University, Waco, Texas, USA

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Erich J Baker Department of Computer Science, Baylor University, Waco, Texas, USA

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Kathleen A Grant Division of Neuroscience, Oregon National Primate Research Center, Oregon Health and Science University, Beaverton, Oregon, USA

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Russell T Turner Skeletal Biology Laboratory, School of Biological and Population Health Sciences, Oregon State University, Corvallis, Oregon, USA

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Urszula T Iwaniec Skeletal Biology Laboratory, School of Biological and Population Health Sciences, Oregon State University, Corvallis, Oregon, USA

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Insulin-like growth factor 1 (IGF-1) influences bone turnover. Transient decreases in IGF-I levels and/or bioavailability may contribute to the detrimental effects of alcohol on bone. The goals of this non-human primate study were to i) evaluate the 20-h response of bone turnover markers to ethanol consumption and ii) assess how ethanol consumption influences the relationship between IGF-1 and these markers. Osteocalcin (bone formation), carboxyterminal cross-linking telopeptide of type 1 collagen (CTX, bone resorption), IGF-1, and IGF binding protein 1 (IGFBP-1) were measured in plasma from male rhesus macaques (N = 10, 8.4 ± 0.3 years) obtained at 12:00, 16:00, and 06:00 h during two phases: pre-ethanol (alcohol-naïve) and ethanol access. During the ethanol access phase, monkeys consumed 1.5 g/kg/day ethanol (4% w/v) beginning at 10:00 h. Osteocalcin and CTX were lower, and the ratio of osteocalcin to CTX was higher at each time point during ethanol access compared to the pre-ethanol phase. Pre-ethanol marker levels did not vary across time points, but markers varied during ethanol access. IGF-1 levels, but not IGFBP-1 levels, varied during the pre-ethanol phase. In contrast, IGF-1 levels were stable during ethanol access but IGFBP-1 levels varied. There were positive relationships between IGF-1 and turnover markers during the pre-ethanol phase, but not during ethanol access. In conclusion, chronic ethanol consumption reduces levels of bone turnover markers and blocks the normal positive relationship between IGF-1 and turnover markers and alters the normal relationship between IGF-1 and IGFBP-1. These findings support the hypothesis that chronic alcohol consumption leads to growth hormone/IGF-1 resistance.

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Adriana María Belén Abiuso Laboratory of Molecular Endocrinology and Signal Transduction, Instituto de Biología y Medicina Experimental (IBYME-CONICET), Buenos Aires, Argentina

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María Luisa Varela Laboratory of Molecular Endocrinology and Signal Transduction, Instituto de Biología y Medicina Experimental (IBYME-CONICET), Buenos Aires, Argentina

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Trinidad Raices Laboratory of Molecular Endocrinology and Signal Transduction, Instituto de Biología y Medicina Experimental (IBYME-CONICET), Buenos Aires, Argentina

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Griselda Irusta Laboratory of Ovarian Physiology and Tumor Biology, Instituto de Biología y Medicina Experimental (IBYME-CONICET), Buenos Aires, Argentina

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Juan Manuel Lazzati Endocrinology Service, Hospital de Pediatría ‘Prof. Dr. Juan P. Garrahan’, Buenos Aires, Argentina

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Marcos Besio Moreno Laboratory of Molecular Endocrinology and Signal Transduction, Instituto de Biología y Medicina Experimental (IBYME-CONICET), Buenos Aires, Argentina

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Alina Cavallotti Laboratory of Molecular Endocrinology and Signal Transduction, Instituto de Biología y Medicina Experimental (IBYME-CONICET), Buenos Aires, Argentina

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Alicia Belgorosky Endocrinology Service, Hospital de Pediatría ‘Prof. Dr. Juan P. Garrahan’, Buenos Aires, Argentina

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Omar Pedro Pignataro Laboratory of Molecular Endocrinology and Signal Transduction, Instituto de Biología y Medicina Experimental (IBYME-CONICET), Buenos Aires, Argentina
Department of Biological Chemistry, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Buenos Aires, Argentina

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Esperanza Berensztein Endocrinology Service, Hospital de Pediatría ‘Prof. Dr. Juan P. Garrahan’, Buenos Aires, Argentina

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Carolina Mondillo Laboratory of Molecular Endocrinology and Signal Transduction, Instituto de Biología y Medicina Experimental (IBYME-CONICET), Buenos Aires, Argentina

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Recent reports indicate an increase in Leydig cell tumor (LCT) incidence. Radical orchiectomy is the standard therapy in children and adults, although it entails physical and psychosocial side effects. Testis-sparing surgery can be a consideration for benign LCT of 2.5 cm or less in size. Malignant LCTs respond poorly to conventional chemotherapy, so new treatment modalities are needed. In this study, we observed increased histidine decarboxylase expression and pro-angiogenic potential in LCT surgically resected from pediatric patients (fetal to pubertal) vs control samples from patients without endocrine or metabolic disorders which were collected at necropsy. We, therefore, evaluated for the first time the antitumor efficacy of two histidine decarboxylase inhibitors (α-methyl-dl-histidine dihydrochloride (α-MHD) and epigallocatechin gallate (EGCG)), alone and combined with carboplatin, in two preclinical models of LCT. MA-10 and R2C Leydig tumor cells, representing two different LCT subtypes, were used to generate syngeneic and xenograft mouse LCT models, respectively. In the syngeneic model, monotherapy with α-MHD effectively reduced tumor growth and angiogenesis. In the xenografts, which showed co-expression of histidine decarboxylase and CYP19, the combination of EGCG plus carboplatin was the most effective therapy, leading to LCT growth arrest and undetectable levels of plasmatic estradiol. Testicular and body weights remained unaltered. On the basis of this study, histidine decarboxylase may emerge as a novel pharmacological target for LCT treatment.

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Ying Sze Centre for Discovery Brain Sciences, University of Edinburgh, Edinburgh, UK
The Roslin Institute, University of Edinburgh, Easter Bush Campus, Midlothian, UK

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Joana Fernandes The Roslin Institute, University of Edinburgh, Easter Bush Campus, Midlothian, UK

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Zofia M Kołodziejczyk Centre for Discovery Brain Sciences, University of Edinburgh, Edinburgh, UK

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Paula J Brunton Centre for Discovery Brain Sciences, University of Edinburgh, Edinburgh, UK
The Roslin Institute, University of Edinburgh, Easter Bush Campus, Midlothian, UK
Zhejiang University-University of Edinburgh Institute, International Campus, Haining, Zhejiang, P.R. China

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Stress during pregnancy negatively affects the fetus and increases the risk for affective disorders in adulthood. Excess maternal glucocorticoids are thought to mediate fetal programming; however, whether they exert their effects directly or indirectly remains unclear. During pregnancy, protective mechanisms including maternal hypothalamic–pituitary–adrenal (HPA) axis hyporesponsiveness and placental 11β-hydroxysteroid dehydrogenase (11βHSD) type 2, which inactivates glucocorticoids, limit mother-to-fetus glucocorticoid transfer. However, whether repeated stress negatively impacts these mechanisms is not known. Pregnant rats were exposed to repeated social stress on gestational days (GD) 16–20 and several aspects of HPA axis and glucocorticoid regulation, including concentrations of glucocorticoids, gene expression for their receptors (Nr3c1, Nr3c2), receptor chaperones (Fkbp51, Fkbp52) and enzymes that control local glucocorticoid availability (Hsd11b1, Hsd11b2), were investigated in the maternal, placental and fetal compartments on GD20. The maternal HPA axis was activated following stress, though the primary driver was vasopressin, rather than corticotropin-releasing hormone. Despite the stress-induced increase in circulating corticosterone in the dams, only a modest increase was detected in the circulation of female fetuses, with no change in the fetal brain of either sex. Moreover, there was no change in the expression of genes that mediate glucocorticoid actions or modulate local concentrations in the fetal brain. In the placenta labyrinth zone, stress increased Hsd11b2 expression only in males and Fkbp51 expression only in females. Our results indicate that any role glucocorticoids play in fetal programming is likely indirect, perhaps through sex-dependent alterations in placental gene expression, rather than exerting effects via direct crossover into the fetal brain.

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Juan Bernal Instituto de Investigaciones Biomedicas Alberto Sols, Consejo Superior de Investigaciones Científicas (CSIC) and Universidad Autónoma de Madrid, Madrid, Spain

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Beatriz Morte Center for Biomedical Research on Rare Diseases (CIBERER), Instituto de Salud Carlos III, Madrid, Spain

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Diego Diez Immunology Frontier Research Center, Osaka University, Osaka, Japan

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Brain development is critically dependent on the timely supply of thyroid hormones. The thyroid hormone transporters are central to the action of thyroid hormones in the brain, facilitating their passage through the blood–brain barrier. Mutations of the monocarboxylate transporter 8 (MCT8) cause the Allan–Herndon–Dudley syndrome, with altered thyroid hormone concentrations in the blood and profound neurological impairment and intellectual deficit. Mouse disease models have revealed interplay between transport, deiodination, and availability of T3 to receptors in specific cells. However, the mouse models are not satisfactory, given the fundamental differences between the mouse and human brains. The goal of the present work is to review human neocortex development in the context of thyroid pathophysiology. Recent developments in single-cell transcriptomic approaches aimed at the human brain make it possible to profile the expression of thyroid hormone regulators in single-cell RNA-Seq datasets of the developing human neocortex. The data provide novel insights into the specific cellular expression of thyroid hormone transporters, deiodinases, and receptors.

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Gabriel O de Souza Departamento de Fisiologia e Biofisica, Instituto de Ciencias Biomedicas, Universidade de Sao Paulo, Sao Paulo, Sao Paulo, Brazil

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Fernanda M Chaves Departamento de Fisiologia e Biofisica, Instituto de Ciencias Biomedicas, Universidade de Sao Paulo, Sao Paulo, Sao Paulo, Brazil

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Josiane N Silva Departamento de Anatomia, Instituto de Ciencias Biomedicas, Universidade de Sao Paulo, Sao Paulo, Sao Paulo, Brazil

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João A B Pedroso Departamento de Fisiologia e Biofisica, Instituto de Ciencias Biomedicas, Universidade de Sao Paulo, Sao Paulo, Sao Paulo, Brazil

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Martin Metzger Departamento de Fisiologia e Biofisica, Instituto de Ciencias Biomedicas, Universidade de Sao Paulo, Sao Paulo, Sao Paulo, Brazil

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Renata Frazão Departamento de Anatomia, Instituto de Ciencias Biomedicas, Universidade de Sao Paulo, Sao Paulo, Sao Paulo, Brazil

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Jose Donato Departamento de Fisiologia e Biofisica, Instituto de Ciencias Biomedicas, Universidade de Sao Paulo, Sao Paulo, Sao Paulo, Brazil

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Recent studies indicated an important role of connexins, gap junction proteins, in the regulation of metabolism. However, most of these studies focused on the glial expression of connexins, whereas the actions of connexins in neurons are still poorly investigated. Thus, the present study had the objective to investigate the possible involvement of gap junctions, and in particular connexin 43 (CX43), for the central regulation of energy homeostasis. Initially, we demonstrated that hypothalamic CX43 expression was suppressed in fasted mice. Using whole-cell patch-clamp recordings, we showed that pharmacological blockade of gap junctions induced hyperpolarization and decreased the frequency of action potentials in 50–70% of agouti-related protein (AgRP)-expressing neurons, depending on the blocker used (carbenoxolone disodium, TAT-Gap19 or Gap 26). When recordings were performed with a biocytin-filled pipette, this intercellular tracer was detected in surrounding cells. Then, an AgRP-specific CX43 knockout (AgRPΔCX43) mouse was generated. AgRPΔCX43 mice exhibited no differences in body weight, adiposity, food intake, energy expenditure and glucose homeostasis. Metabolic responses to 24 h fasting or during refeeding were also not altered in AgRPΔCX43 mice. However, AgRPΔCX43 male, but not female mice, exhibited a partial protection against high-fat diet-induced obesity, even though no significant changes in energy intake or expenditure were detected. In summary, our findings indicate that gap junctions regulate the activity of AgRP neurons, and AgRP-specific CX43 ablation is sufficient to mildly prevent diet-induced obesity specifically in males.

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Jordan E Hamden Department of Zoology, University of British Columbia, Vancouver, British Columbia, Canada
Djavad Mowafaghian Centre for Brain Health, University of British Columbia, Vancouver, British Columbia, Canada

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Katherine M Gray Department of Psychology, University of British Columbia, Vancouver, British Columbia, Canada
Faculty of Medicine, University of British Columbia, Vancouver, British Columbia, Canada

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Melody Salehzadeh Department of Zoology, University of British Columbia, Vancouver, British Columbia, Canada
Djavad Mowafaghian Centre for Brain Health, University of British Columbia, Vancouver, British Columbia, Canada

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Kiran K Soma Department of Zoology, University of British Columbia, Vancouver, British Columbia, Canada
Djavad Mowafaghian Centre for Brain Health, University of British Columbia, Vancouver, British Columbia, Canada
Department of Psychology, University of British Columbia, Vancouver, British Columbia, Canada
Graduate Program in Neuroscience, University of British Columbia, Vancouver, British Columbia, Canada

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The profound programming effects of early life stress (ELS) on brain and behavior are thought to be primarily mediated by adrenal glucocorticoids (GCs). However, in mice, stressors are often administered between postnatal days 2 and 12 (PND2–12), during the stress hyporesponsive period (SHRP), when adrenal GC production is greatly reduced at baseline and in response to stressors. During the SHRP, specific brain regions produce GCs at baseline, but it is unknown if brain GC production increases in response to stressors. We treated mice at PND1 (pre-SHRP), PND5 (SHRP), PND9 (SHRP), and PND13 (post-SHRP) with an acute stressor (isoflurane anesthesia), vehicle control (oxygen), or neither (baseline). We measured a panel of progesterone and six GCs in the blood, hippocampus, cerebral cortex, and hypothalamus via liquid chromatography tandem mass spectrometry. At PND1, baseline corticosterone levels were high and did not increase in response to stress. At PND5, baseline corticosterone levels were very low, increases in brain corticosterone levels were greater than the increase in blood corticosterone levels, and stress had region-specific effects. At PND9, baseline corticosterone levels were low and increased similarly and moderately in response to stress. At PND13, blood corticosterone levels were higher than those at PND9, and corticosterone levels were higher in blood than in brain regions. These data illustrate the rapid and profound changes in stress physiology during neonatal development and suggest that neurosteroid production is a possible mechanism by which ELS has enduring effects on brain and behavior.

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James I Raeside Department of Biomedical Sciences, Ontario Veterinary College, University of Guelph, Guelph, Ontario, Canada

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Heather L Christie Department of Biomedical Sciences, Ontario Veterinary College, University of Guelph, Guelph, Ontario, Canada

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Current heightened recognition of the importance of sulfated steroids led to the examination of conjugates in media from incubations of estrogens in tissues from the reproductive tract of stallions. Previously, we had reported a ‘new’ unidentified metabolite of estrone (E1) and [3H]-E1, located between 17β-estradiol (E2) and E1 reference standards on chromatography (HPLC) and identified tentatively as a stable 5α,6α-estrone epoxide. Stallion tissues were minced and incubated for 2 h with [3H]-E1 (1 × 106 cpm). Solid-phase extraction of unconjugated and conjugated steroids from media was followed by liquid scintillation counting (LSC), where radioactivity was mostly in the conjugate fractions (>80%). HPLC of conjugated steroids used an isocratic solvent system of acetonitrile/water (8:92) at 700 µL/min with detection by LSC. A radioactive peak between reference standards of E1 and E2 sulfates was examined, after solvolysis, in a second solvent system. Sulfated steroids yielded largely E1, whereas acid treatment of the unconjugated E1 epoxide had earlier formed 6α-OH-E1 almost exclusively. With sulfatase enzyme, at neutral pH, radioactivity was also seen mostly as E1 with trace amounts of polar material. Reduction with KBH4, however, led also to desulfation; radioactivity had alignment with E2 but even more had low retention times as for 6α/6β-OH-E2. These findings point to a different hydrolysis for desulfation; even more, they reveal an additional oxygen atom at C6 and are supportive of biological formation of 5α,6α-epoxides of E1 and E2. As possible alternatives to catechol estrogens, implicated in cancer, the ‘new’ estrogen metabolites and their sulfated forms may have special interest.

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Carmen Corciulo Centre for Bone and Arthritis Research, Department of Rheumatology and Inflammation Research, Institute of Medicine, Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden
Sahlgrenska Osteoporosis Centre, Centre for Bone and Arthritis Research, Department of Internal Medicine and Clinical Nutrition, Institute of Medicine, Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden

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Julia M Scheffler Centre for Bone and Arthritis Research, Department of Rheumatology and Inflammation Research, Institute of Medicine, Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden
Sahlgrenska Osteoporosis Centre, Centre for Bone and Arthritis Research, Department of Internal Medicine and Clinical Nutrition, Institute of Medicine, Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden

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Piotr Humeniuk Centre for Bone and Arthritis Research, Department of Rheumatology and Inflammation Research, Institute of Medicine, Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden
Sahlgrenska Osteoporosis Centre, Centre for Bone and Arthritis Research, Department of Internal Medicine and Clinical Nutrition, Institute of Medicine, Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden

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Alicia Del Carpio Pons Centre for Bone and Arthritis Research, Department of Rheumatology and Inflammation Research, Institute of Medicine, Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden
Sahlgrenska Osteoporosis Centre, Centre for Bone and Arthritis Research, Department of Internal Medicine and Clinical Nutrition, Institute of Medicine, Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden

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Alexandra Stubelius Division of Chemical Biology, Department of Biology and Biological Engineering, Chalmers University of Technology, Gothenburg, Sweden

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Ula Von Mentzer Division of Chemical Biology, Department of Biology and Biological Engineering, Chalmers University of Technology, Gothenburg, Sweden

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Christina Drevinge Centre for Bone and Arthritis Research, Department of Rheumatology and Inflammation Research, Institute of Medicine, Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden
Sahlgrenska Osteoporosis Centre, Centre for Bone and Arthritis Research, Department of Internal Medicine and Clinical Nutrition, Institute of Medicine, Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden

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Aidan Barrett Centre for Bone and Arthritis Research, Department of Rheumatology and Inflammation Research, Institute of Medicine, Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden
Sahlgrenska Osteoporosis Centre, Centre for Bone and Arthritis Research, Department of Internal Medicine and Clinical Nutrition, Institute of Medicine, Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden

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Sofia Wüstenhagen Centre for Bone and Arthritis Research, Department of Rheumatology and Inflammation Research, Institute of Medicine, Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden
Sahlgrenska Osteoporosis Centre, Centre for Bone and Arthritis Research, Department of Internal Medicine and Clinical Nutrition, Institute of Medicine, Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden

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Matti Poutanen Sahlgrenska Osteoporosis Centre, Centre for Bone and Arthritis Research, Department of Internal Medicine and Clinical Nutrition, Institute of Medicine, Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden
Institute of Biomedicine, Research Centre for Integrative Physiology and Pharmacology, Turku Center for Disease Modeling, University of Turku, Turku, Finland

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

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Marie K Lagerquist Sahlgrenska Osteoporosis Centre, Centre for Bone and Arthritis Research, Department of Internal Medicine and Clinical Nutrition, Institute of Medicine, Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden

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Ulrika Islander Centre for Bone and Arthritis Research, Department of Rheumatology and Inflammation Research, Institute of Medicine, Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden
Sahlgrenska Osteoporosis Centre, Centre for Bone and Arthritis Research, Department of Internal Medicine and Clinical Nutrition, Institute of Medicine, Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden

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Among patients with knee osteoarthritis (OA), postmenopausal women are over-represented. The purpose of this study was to determine whether deficiency of female sex steroids affects OA progression and to evaluate the protective effect of treatment with a physiological dose of 17β-estradiol (E2) on OA progression using a murine model. Ovariectomy (OVX) of female mice was used to mimic a postmenopausal state. OVX or sham-operated mice underwent surgery for destabilization of the medial meniscus (DMM) to induce OA. E2 was administered in a pulsed manner for 2 and 8 weeks. OVX of OA mice did not influence the cartilage phenotype or synovial thickness, while both cortical and trabecular subchondral bone mineral density (BMD) decreased after OVX compared with sham-operated mice at 8 weeks post-DMM surgery. Additionally, OVX mice displayed decreased motor activity, reduced threshold of pain sensitivity, and increased number of T cells in the inguinal lymph nodes compared to sham-operated mice 2 weeks after OA induction. Eight weeks of treatment with E2 prevented cartilage damage and thickening of the synovium in OVX OA mice. The motor activity was improved after E2 replacement at the 2 weeks time point, which was also associated with lower pain sensitivity in the OA paw. E2 treatment protected against OVX-induced loss of subchondral trabecular bone. The number of T cells in the inguinal lymph nodes was reduced by E2 treatment after 8 weeks. This study demonstrates that treatment with a physiological dose of E2 exerts a protective role by reducing OA symptoms.

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Ryan A Lafferty Biomedical Sciences Research Institute, Centre for Diabetes, Ulster University, Coleraine, Northern Ireland, UK

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Laura M McShane Biomedical Sciences Research Institute, Centre for Diabetes, Ulster University, Coleraine, Northern Ireland, UK

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Zara J Franklin Biomedical Sciences Research Institute, Centre for Diabetes, Ulster University, Coleraine, Northern Ireland, UK

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Peter R Flatt Biomedical Sciences Research Institute, Centre for Diabetes, Ulster University, Coleraine, Northern Ireland, UK

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Finbarr P M O’Harte Biomedical Sciences Research Institute, Centre for Diabetes, Ulster University, Coleraine, Northern Ireland, UK

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Nigel Irwin Biomedical Sciences Research Institute, Centre for Diabetes, Ulster University, Coleraine, Northern Ireland, UK

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Discerning modification to the amino acid sequence of native glucagon can generate specific glucagon receptor (GCGR) antagonists, that include desHis1Pro4Glu9-glucagon and the acylated form desHis1Pro4Glu9(Lys12PAL)-glucagon. In the current study, we have evaluated the metabolic benefits of once-daily injection of these peptide-based GCGR antagonists for 18 days in insulin-resistant high-fat-fed (HFF) mice with streptozotocin (STZ)-induced insulin deficiency, namely HFF-STZ mice. Administration of desHis1Pro4Glu9-glucagon moderately (P < 0.05) decreased STZ-induced elevations of food intake. Body weight was not different between groups of HFF-STZ mice and both treatment interventions delayed (P < 0.05) the onset of hyperglycaemia. The treatments reduced (P < 0.05–P < 0.001) circulating and pancreatic glucagon, whilst desHis1Pro4Glu9(Lys12PAL)-glucagon also substantially increased (P < 0.001) pancreatic insulin stores. Oral glucose tolerance was appreciably improved (P < 0.05) by both antagonists, despite the lack of augmentation of glucose-stimulated insulin release. Interestingly, positive effects on i.p. glucose tolerance were less obvious suggesting important beneficial effects on gut function. Metabolic benefits were accompanied by decreased (P < 0.05–P < 0.01) locomotor activity and increases (P < 0.001) in energy expenditure and respiratory exchange ratio in both treatment groups. In addition, desHis1Pro4Glu9-glucagon increased (P < 0.01–P < 0.001) O2 consumption and CO2 production. Together, these data provide further evidence that peptidic GCGR antagonists are effective treatment options for obesity-driven forms of diabetes, even when accompanied by insulin deficiency.

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