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MARY DYSON
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J. JOSEPH
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SUMMARY

The effects of oestradiol-17β and progesterone on tissue regeneration in the rabbit's ear were investigated. One square centimetre of tissue was excised through the whole thickness of the ear under pentobarbitone anaesthesia, and the rate of replacement, in terms of increase in surface area of the regenerated tissue, was recorded at 7-day intervals up to 49 days. The hormones were administered by subcutaneous injection five times weekly during this period. In females, oestradiol in individual doses of 10 μg/3 kg body weight stimulated regenerative growth significantly; 100 μg had no effect, and 1000 μg was inhibitory. In males, injections of 10 μg oestradiol had no significant effect on regeneration, while 100 μg was inhibitory. Progesterone stimulated regeneration in females at a dose of 100 μg/3 kg body weight, and in both males and females at 1000 μg/3 kg. Tissues were examined at 49 days for changes produced by the experimental regimes, and the effects of 17-oxosteroid excretion during the experimental period were also measured. Liver damage was produced in females by oestradiol at the 1000 μg/3 kg level and in males at the 100 μg dose; in both groups it was accompanied by loss of weight. None of the other treatments had toxic effects. The regeneration blastemata of animals treated with progesterone were better vascularized than either those of the untreated controls or of animals treated with oestradiol. The possible significance of these results is discussed.

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Leah Yogev
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J. R. Gibber
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Joseph Terkel
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At mid-pregnancy in the rat, episodic secretion of pituitary'prolactin ceases when the placenta is sufficiently developed. At this time, sufficient placental lactogen is secreted by the placenta to inhibit prolactin secretion. The present study tested whether the fully developed placenta at mid-pregnancy can inhibit prolactin secreted by a donor pituitary gland implanted under the kidney capsule. Three pituitary glands were implanted in rats on day 7 of pregnancy; muscle fragments were implanted in controls. Blood was collected during the first and second halves of pregnancy. It was found that prolactin concentrations in the animals with the pituitary implants were high on days 9 and 10 of pregnancy and remained raised during the second half of pregnancy while in control animals nocturnal surges were absent in the second half of pregnancy, the last one occurring on day 10. This observation indicates that the placental hormone cannot act directly on the pituitary gland to inhibit prolactin secretion, but presumably exerts its suppressive effect on prolactin secretion through the hypothalamus.

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Barbara C Fam Department of Medicine (Austin Health), Austin Hospital, University of Melbourne, Level 7, Lance Townsend Building, Studley Road, Heidelberg, Victoria 3084, Australia

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Laura J Rose Department of Medicine (Austin Health), Austin Hospital, University of Melbourne, Level 7, Lance Townsend Building, Studley Road, Heidelberg, Victoria 3084, Australia

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Rebecca Sgambellone Department of Medicine (Austin Health), Austin Hospital, University of Melbourne, Level 7, Lance Townsend Building, Studley Road, Heidelberg, Victoria 3084, Australia

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Zheng Ruan Department of Medicine (Austin Health), Austin Hospital, University of Melbourne, Level 7, Lance Townsend Building, Studley Road, Heidelberg, Victoria 3084, Australia

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Joseph Proietto Department of Medicine (Austin Health), Austin Hospital, University of Melbourne, Level 7, Lance Townsend Building, Studley Road, Heidelberg, Victoria 3084, Australia

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Sofianos Andrikopoulos Department of Medicine (Austin Health), Austin Hospital, University of Melbourne, Level 7, Lance Townsend Building, Studley Road, Heidelberg, Victoria 3084, Australia

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Skeletal muscle insulin resistance is a major characteristic underpinning type 2 diabetes. Impairments in the insulin responsiveness of the glucose transporter, Glut4 (Slc2a4), have been suggested to be a contributing factor to this disturbance. We have produced muscle-specific Glut4 knockout (KO) mice using Cre/LoxP technology on a C57BL6/J background and shown undetectable levels of GLUT4 in both skeletal muscle and heart. Our aim was to determine whether complete deletion of muscle GLUT4 does in fact lead to perturbations in glucose homoeostasis. Glucose tolerance, glucose turnover and 2-deoxyglucose uptake into muscle and fat under basal and insulin-stimulated conditions were assessed in 12-week-old KO and control mice using the oral glucose tolerance test (OGTT) and hyperinsulinaemic/euglycaemic clamp respectively. KO mice weighed ∼17% less and had significantly heavier hearts compared with control mice. Basally, plasma glucose and plasma insulin were significantly lower in the KO compared with control mice, which conferred normal glucose tolerance. Despite the lack of GLUT4 in the KO mouse muscle, glucose uptake was not impaired in skeletal muscle but was reduced in heart under insulin-stimulated conditions. Neither GLUT1 nor GLUT12 protein levels were altered in the skeletal muscle or heart tissue of our KO mice. High-fat feeding did not alter glucose tolerance in the KO mice but led to elevated plasma insulin levels during the glucose tolerance test. Our study demonstrates that deletion of muscle GLUT4 does not adversely affect glucose disposal and glucose tolerance and that compensation from other transporters may contribute to this unaltered homoeostasis of glucose.

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A. M. GAWIENOWSKI
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P. J. ORSULAK
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MARIA STACEWICZ-SAPUNTZAKIS
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B. M. JOSEPH
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SUMMARY

Female rats consistently preferred the odour of male rat preputial gland compared with that of foot pads, submaxillary-sublingual glands, coagulating glands, liver, fat or muscle. Both saline homogenates and ether extracts were effective. Female rats did not respond to the odour of female preputial extract and they preferred the odour of normal male preputial extract to that from castrated rats. The pheromone was not associated with the fatty acids of the preputial extract. The fractionation of the volatile components of preputial extracts by gas chromatography revealed that most of the biological activity resided in a specific fraction.

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Meghan F Hogan Division of Metabolism, Endocrinology and Nutrition, VA Puget Sound Health Care System, Seattle, Washington, USA
Department of Medicine, University of Washington, Seattle, Washington, USA

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Daryl J Hackney Division of Metabolism, Endocrinology and Nutrition, VA Puget Sound Health Care System, Seattle, Washington, USA

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Alfred C Aplin Division of Metabolism, Endocrinology and Nutrition, VA Puget Sound Health Care System, Seattle, Washington, USA

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Thomas O Mundinger Department of Medicine, University of Washington, Seattle, Washington, USA

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Megan J Larmore Department of Comparative Medicine, University of Washington, Seattle, Washington, USA

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Joseph J Castillo Division of Metabolism, Endocrinology and Nutrition, VA Puget Sound Health Care System, Seattle, Washington, USA
Department of Medicine, University of Washington, Seattle, Washington, USA

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Nathalie Esser Division of Metabolism, Endocrinology and Nutrition, VA Puget Sound Health Care System, Seattle, Washington, USA
Department of Medicine, University of Washington, Seattle, Washington, USA

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Sakeneh Zraika Division of Metabolism, Endocrinology and Nutrition, VA Puget Sound Health Care System, Seattle, Washington, USA
Department of Medicine, University of Washington, Seattle, Washington, USA

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Rebecca L Hull Division of Metabolism, Endocrinology and Nutrition, VA Puget Sound Health Care System, Seattle, Washington, USA
Department of Medicine, University of Washington, Seattle, Washington, USA

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Islet endothelial cells produce paracrine factors important for islet beta-cell function and survival. Under conditions of type 2 diabetes, islet endothelial cells exhibit a dysfunctional phenotype including increased expression of genes involved in cellular adhesion and inflammation. We sought to determine whether treatment of hyperglycemia with the sodium glucose co-transporter 2 inhibitor empagliflozin, either alone or in combination with metformin, would improve markers of endothelial cell function in islets, assessed ex vivo, and if such an improvement is associated with improved insulin secretion in a mouse model of diabetes in vivo. For these studies, db/db diabetic mice and non-diabetic littermate controls were treated for 6 weeks with empagliflozin or metformin, either alone or in combination. For each treatment group, expression of genes indicative of islet endothelial dysfunction was quantified. Islet endothelial and beta-cell area was assessed by morphometry of immunochemically stained pancreas sections. Measurements of plasma glucose and insulin secretion during an intravenous glucose tolerance test were performed on vehicle and drug treated diabetic animals. We found that expression of endothelial dysfunction marker genes is markedly increased in diabetic mice. Treatment with either empagliflozin or metformin lowered expression of the dysfunction marker genes ex vivo, which correlated with improved glycemic control, and increased insulin release in vivo. Empagliflozin treatment was more effective than metformin alone, with a combination of the two drugs demonstrating the greatest effects. Improving islet endothelial function through strategies such as empagliflozin/metformin treatment may provide an effective approach for improving insulin release in human type 2 diabetes.

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T S McQuaid Department of Biomedical Sciences, Atlantic Veterinary College, University of Prince Edward Island, 550 University Avenue, Charlottetown, Prince Edward, C1A 4P3 Canada
Departments of Medicine and Physiology, University of Toronto, 1 Kings College Circle, Toronto, Ontario, M5F 1A8 Canada

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M C Saleh Department of Biomedical Sciences, Atlantic Veterinary College, University of Prince Edward Island, 550 University Avenue, Charlottetown, Prince Edward, C1A 4P3 Canada
Departments of Medicine and Physiology, University of Toronto, 1 Kings College Circle, Toronto, Ontario, M5F 1A8 Canada

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J W Joseph Department of Biomedical Sciences, Atlantic Veterinary College, University of Prince Edward Island, 550 University Avenue, Charlottetown, Prince Edward, C1A 4P3 Canada
Departments of Medicine and Physiology, University of Toronto, 1 Kings College Circle, Toronto, Ontario, M5F 1A8 Canada

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A Gyulkhandanyan Department of Biomedical Sciences, Atlantic Veterinary College, University of Prince Edward Island, 550 University Avenue, Charlottetown, Prince Edward, C1A 4P3 Canada
Departments of Medicine and Physiology, University of Toronto, 1 Kings College Circle, Toronto, Ontario, M5F 1A8 Canada

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J E Manning-Fox Department of Biomedical Sciences, Atlantic Veterinary College, University of Prince Edward Island, 550 University Avenue, Charlottetown, Prince Edward, C1A 4P3 Canada
Departments of Medicine and Physiology, University of Toronto, 1 Kings College Circle, Toronto, Ontario, M5F 1A8 Canada

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J D MacLellan Department of Biomedical Sciences, Atlantic Veterinary College, University of Prince Edward Island, 550 University Avenue, Charlottetown, Prince Edward, C1A 4P3 Canada
Departments of Medicine and Physiology, University of Toronto, 1 Kings College Circle, Toronto, Ontario, M5F 1A8 Canada

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M B Wheeler Department of Biomedical Sciences, Atlantic Veterinary College, University of Prince Edward Island, 550 University Avenue, Charlottetown, Prince Edward, C1A 4P3 Canada
Departments of Medicine and Physiology, University of Toronto, 1 Kings College Circle, Toronto, Ontario, M5F 1A8 Canada

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C B Chan Department of Biomedical Sciences, Atlantic Veterinary College, University of Prince Edward Island, 550 University Avenue, Charlottetown, Prince Edward, C1A 4P3 Canada
Departments of Medicine and Physiology, University of Toronto, 1 Kings College Circle, Toronto, Ontario, M5F 1A8 Canada

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We investigated whether an increase in cAMP could normalize glucose-stimulated insulin secretion (GSIS) in uncoupling protein-2 (UCP2) overexpressing (ucp2-OE) β-cells. Indices of β-cell (β-TC-6f7 cells and rodent islets) function were measured after induction of ucp2, in the presence or absence of cAMP-stimulating agents, analogs, or inhibitors. Islets of ob/ob mice had improved glucose-responsiveness in the presence of forskolin. Rat islets overexpressing ucp2 had significantly lower GSIS than controls. Acutely, the protein kinase A (PKA) and epac pathway stimulant forskolin normalized insulin secretion in ucp2-OE rat islets and β-TC-6f7 β-cells, an effect blocked by specific PKA inhibitors but not mimicked by epac agonists. However, there was no effect of ucp2-OE on cAMP concentrations or PKA activity. In ucp2-OE islets, forskolin inhibited ATP-dependent potassium (KATP) channel currents and 86Rb+ efflux, indicative of KATP block. Likewise, forskolin application increased intracellular Ca2+, which could account for its stimulatory effects on insulin secretion. Chronic exposure to forskolin increased ucp2 mRNA and exaggerated basal secretion but not GSIS. In mice deficient in UCP2, there was no augmentation of either cAMP content or cAMP-dependent insulin secretion. Thus, elevating cellular cAMP can reverse the deficiency in GSIS invoked by ucp2-OE, at least partly through PKA-mediated effects on the KATP channel.

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Hong Lan Cardiovascular and Metabolic Disease Research, Drug Safety,, Departments of

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Galya Vassileva Cardiovascular and Metabolic Disease Research, Drug Safety,, Departments of

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Aaron Corona Cardiovascular and Metabolic Disease Research, Drug Safety,, Departments of

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Li Liu Cardiovascular and Metabolic Disease Research, Drug Safety,, Departments of

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Hana Baker Cardiovascular and Metabolic Disease Research, Drug Safety,, Departments of

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Andrei Golovko Cardiovascular and Metabolic Disease Research, Drug Safety,, Departments of

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Susan J Abbondanzo Cardiovascular and Metabolic Disease Research, Drug Safety,, Departments of

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Weiwen Hu Cardiovascular and Metabolic Disease Research, Drug Safety,, Departments of

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Shijun Yang Cardiovascular and Metabolic Disease Research, Drug Safety,, Departments of

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Yun Ning Cardiovascular and Metabolic Disease Research, Drug Safety,, Departments of

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Robert A Del Vecchio Cardiovascular and Metabolic Disease Research, Drug Safety,, Departments of

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Frederique Poulet Cardiovascular and Metabolic Disease Research, Drug Safety,, Departments of

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Maureen Laverty Cardiovascular and Metabolic Disease Research, Drug Safety,, Departments of

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Eric L Gustafson Cardiovascular and Metabolic Disease Research, Drug Safety,, Departments of

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Joseph A Hedrick Cardiovascular and Metabolic Disease Research, Drug Safety,, Departments of

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Timothy J Kowalski Cardiovascular and Metabolic Disease Research, Drug Safety,, Departments of

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G protein-coupled receptor 119 (GPR119) is expressed in pancreatic islets and intestine, and is involved in insulin and incretin hormone release. GPR119-knockout (Gpr119 −/−) mice were reported to have normal islet morphology and normal size, body weight (BW), and fed/fasted glucose levels. However, the physiological function of GPR119 and its role in maintaining glucose homeostasis under metabolic stress remain unknown. Here, we report the phenotypes of an independently generated line of Gpr119 −/− mice under basal and high-fat diet (HFD)-induced obesity. Under low-fat diet feeding, Gpr119 −/− mice show normal plasma glucose and lipids, but have lower BWs and lower post-prandial levels of active glucagon-like peptide 1 (GLP-1). Nutrient-stimulated GLP-1 release is attenuated in Gpr119 −/− mice, suggesting that GPR119 plays a role in physiological regulation of GLP-1 secretion. Under HFD-feeding, both Gpr119 + / + and Gpr119 −/− mice gain weight similarly, develop hyperinsulinemia and hyperleptinemia, but not hyperglycemia or dyslipidemia. Glucose and insulin tolerance tests did not reveal a genotypic difference. These data show that GPR119 is not essential for the maintenance of glucose homeostasis. Moreover, we found that oleoylethanolamide (OEA), reported as a ligand for GPR119, was able to suppress food intake in both Gpr119 + / + and Gpr119 −/− mice, indicating that GPR119 is not required for the hypophagic effect of OEA. Our results demonstrate that GPR119 is important for incretin and insulin secretion, but not for appetite suppression.

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Thomas M Braxton School of Biosciences, Cardiff University, Cardiff, UK

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Dionne E A Sarpong School of Biosciences, Cardiff University, Cardiff, UK

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Janine L Dovey School of Biosciences, Cardiff University, Cardiff, UK

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Anne Guillou IGF, CNRS, INSERM, University of Montpellier, Montpellier, France

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Bronwen A J Evans School of Medicine, Cardiff University, Cardiff, UK

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Juan M Castellano Physiology Section, Faculty of Medicine, University of Cordoba, and Instituto Maimonides de Investigacion Biomedica de Cordoba (IMBIC), Cordoba, Spain

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Bethany E Keenan School of Engineering, Cardiff University, Cardiff, UK

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Saja Baraghithy Obesity and Metabolism Laboratory, Institute for Drug Research, School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem, Israel

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Sam L Evans School of Engineering, Cardiff University, Cardiff, UK

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Manuel Tena-Sempere Physiology Section, Faculty of Medicine, University of Cordoba, and Instituto Maimonides de Investigacion Biomedica de Cordoba (IMBIC), Cordoba, Spain
CIBER Fisiopatologia de la Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III, Cordoba, Spain

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Patrice Mollard IGF, CNRS, INSERM, University of Montpellier, Montpellier, France

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Joseph Tam Obesity and Metabolism Laboratory, Institute for Drug Research, School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem, Israel

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Timothy Wells School of Biosciences, Cardiff University, Cardiff, UK

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Human Prader–Willi syndrome (PWS) is characterised by impairments of multiple systems including the growth hormone (GH) axis and skeletal growth. To address our lack of knowledge of the influence of PWS on skeletal integrity in mice, we have characterised the endocrine and skeletal phenotype of the PWS-IC del mouse model for ‘full’ PWS and determined the impact of thermoneutrality. Tibial length, epiphyseal plate width and marrow adiposity were reduced by 6, 18 and 79% in male PWS-IC del mice, with osteoclast density being unaffected. Similar reductions in femoral length accompanied a 32% reduction in mid-diaphyseal cortical diameter. Distal femoral Tb.N was reduced by 62%, with individual trabeculae being less plate-like and the lattice being more fragmented (Tb.Pf increased by 63%). Cortical strength (ultimate moment) was reduced by 26% as a result of reductions in calcified tissue strength and the geometric contribution. GH and prolactin contents in PWS-IC del pituitaries were reduced in proportion to their smaller pituitary size, with circulating IGF-1 concentration reduced by 37–47%. Conversely, while pituitary luteinising hormone content was halved, circulating gonadotropin concentrations were unaffected. Although longitudinal growth, marrow adiposity and femoral geometry were unaffected by thermoneutrality, strengthened calcified tissue reversed the weakened cortex of PWS-IC del femora. While underactivity of the GH axis may be due to loss of Snord116 expression and impaired limb bone geometry and strength due to loss of Magel2 expression, comprehensive analysis of skeletal integrity in the single gene deletion models is required. Our data imply that thermoneutrality may ameliorate the elevated fracture risk associated with PWS.

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Iwona J Bujalska Department of Endocrinology, Division of Medical Sciences,
Academic Unit of Ophthalmology, Division of Immunity and Infection, University of Birmingham,
Birmingham and Midland Eye Centre, Dudley Road, Birmingham B18 7QU, UK

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Omar M Durrani Department of Endocrinology, Division of Medical Sciences,
Academic Unit of Ophthalmology, Division of Immunity and Infection, University of Birmingham,
Birmingham and Midland Eye Centre, Dudley Road, Birmingham B18 7QU, UK

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Joseph Abbott Department of Endocrinology, Division of Medical Sciences,
Academic Unit of Ophthalmology, Division of Immunity and Infection, University of Birmingham,
Birmingham and Midland Eye Centre, Dudley Road, Birmingham B18 7QU, UK

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Claire U Onyimba Department of Endocrinology, Division of Medical Sciences,
Academic Unit of Ophthalmology, Division of Immunity and Infection, University of Birmingham,
Birmingham and Midland Eye Centre, Dudley Road, Birmingham B18 7QU, UK

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Pamela Khosla Department of Endocrinology, Division of Medical Sciences,
Academic Unit of Ophthalmology, Division of Immunity and Infection, University of Birmingham,
Birmingham and Midland Eye Centre, Dudley Road, Birmingham B18 7QU, UK

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Areeb H Moosavi Department of Endocrinology, Division of Medical Sciences,
Academic Unit of Ophthalmology, Division of Immunity and Infection, University of Birmingham,
Birmingham and Midland Eye Centre, Dudley Road, Birmingham B18 7QU, UK

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Tristan T Q Reuser Department of Endocrinology, Division of Medical Sciences,
Academic Unit of Ophthalmology, Division of Immunity and Infection, University of Birmingham,
Birmingham and Midland Eye Centre, Dudley Road, Birmingham B18 7QU, UK

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Paul M Stewart Department of Endocrinology, Division of Medical Sciences,
Academic Unit of Ophthalmology, Division of Immunity and Infection, University of Birmingham,
Birmingham and Midland Eye Centre, Dudley Road, Birmingham B18 7QU, UK

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Jeremy W Tomlinson Department of Endocrinology, Division of Medical Sciences,
Academic Unit of Ophthalmology, Division of Immunity and Infection, University of Birmingham,
Birmingham and Midland Eye Centre, Dudley Road, Birmingham B18 7QU, UK

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Elizabeth A Walker Department of Endocrinology, Division of Medical Sciences,
Academic Unit of Ophthalmology, Division of Immunity and Infection, University of Birmingham,
Birmingham and Midland Eye Centre, Dudley Road, Birmingham B18 7QU, UK

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Saaeha Rauz Department of Endocrinology, Division of Medical Sciences,
Academic Unit of Ophthalmology, Division of Immunity and Infection, University of Birmingham,
Birmingham and Midland Eye Centre, Dudley Road, Birmingham B18 7QU, UK

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Glucocorticoids (GCs) have a profound effect on adipose biology increasing tissue mass causing central obesity. The pre-receptor regulation of GCs by 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) that activates cortisol from cortisone has been postulated as a fundamental mechanism underlying the metabolic syndrome mediating adipocyte hyperplasia and hypertrophy in the omental (OM) depot. Orbital adipose tissue (OF) is the site of intense inflammation and tissue remodelling in several orbital inflammatory disease states. In this study, we describe features of the GC metabolic pathways in normal human OF depot and compare it with subcutaneous (SC) and OM depots. Using an automated histological characterisation technique, OF adipocytes were found to be significantly smaller (parameters: area, maximum diameter and perimeter) than OM and SC adipocytes (P<0.001). Although immunohistochemical analyses demonstrated resident CD68+ cells in all three whole tissue adipose depots, OF CD68 mRNA and protein expression exceeded that of OM and SC (mRNA, P<0.05; protein, P<0.001). In addition, there was higher expression of glucocorticoid receptor (GR)α mRNA in the OF whole tissue depot (P<0.05). Conversely, 11β-HSD1 mRNA together with the markers of late adipocyte differentiation (FABP4 and G3PDH) were significantly lower in OF. Primary cultures of OF preadipocytes demonstrated predominant 11β-HSD1 oxo-reductase activity with minimal dehydrogenase activity. Orbital adipocytes are smaller, less differentiated, and express low levels of 11β-HSD1 but abundant GRα compared with SC and OM. OF harbours a large CD68+ population. These characteristics define an orbital microenvironment that has the potential to respond to sight-threatening orbital inflammatory disease.

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